Topical compositions containing rofecoxib and methods of making and using the same

ABSTRACT

The present disclosure provides topical compositions of rofecoxib and methods of making said compositions. The present disclosure also provides methods of using topical compositions of rofecoxib to treat inflammation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/183,130, filed Feb. 23, 2021, which is continuation of InternationalApplication No. PCT/US2021/012769, filed Jan. 8, 2021, which claimspriority to U.S. Provisional Application No. 62/959,624, filed Jan. 10,2020. Each of the aforementioned applications is incorporated byreference herein in its entirety for all purposes.

FIELD

The disclosure relates to topical compositions containing rofecoxib. Thedisclosure further relates to methods of applying topical compositionscontaining rofecoxib to the skin to alleviate inflammation and pain.

BACKGROUND OF THE INVENTION

Oral non-steroidal anti-inflammatory drugs (NSAIDs) are a mainstay inthe management of inflammatory diseases, including arthritis, bursitis,and tendonitis. NSAIDS exert analgesic, anti-inflammatory andantipyretic effects through inhibition of the cyclooxygenase enzymes,COX-1 and COX-2. NSAIDS are used to reduce pain and inflammation. NSAIDSare however associated with serious potential side effects includingnausea, vomiting, peptic ulcer disease, gastrointestinal bleeding, andcardiovascular events. The side effects of NSAIDS led to the developmentof selective cyclooxygenase-2 (COX-2) inhibitors. Although COX-2inhibitors reduce the risk of gastrointestinal bleeding, COX-2inhibitors are still associated with cardiovascular events. Theselective COX-2 inhibitor rofecoxib exhibits a greater therapeuticefficacy for treating pain than celecoxib and acetaminophen. However,rofecoxib was withdrawn from the market due to an increased risk ofcardiac toxicity associated with long-term use. Therefore, there remainsa need in the art for the development of alternative NSAID formulationsthat effectively treat inflammation and exhibit fewer side effects.

SUMMARY OF THE INVENTION

Topical compositions containing rofecoxib and methods of making andusing the same are described herein. The rofecoxib topical compositionsdescribed herein exhibit a reduced risk of cardiac toxicity compared tooral rofecoxib formulations.

In some embodiments, a topical composition comprising a therapeuticallyeffective amount of rofecoxib dissolved in a solvent system comprisingone or more pharmaceutically acceptable solvents is provided.

In some embodiments, the pharmaceutically acceptable solvent system ofthe topical compositions comprising a therapeutically effective amountof rofecoxib described herein comprise one or more pharmaceuticallyacceptable solvents selected from the group consisting of acetone (AC),2-methylpentane-2,4-diol (M24D), alpha-terpineol (AT), benzyl alcohol(BA), diethyl sebacate (DS), diethylene glycol monoethyl ether (DGME),diisopropyl adipate (DIA), dimethyl sulfoxide (DMSO), ethyl acetate(EA), isopropyl tetradecanoate (IPTD, also called isopropyltetradecanoate), N-methyl-2-pyrrolidone (MP), polyethylene glycol 400(PEG), polysorbate 20 (PS20), polysorbate 80 (PS80), propylene glycoldiacetate (PGD), propylene glycol (PPG), isosorbide dimethyl ether, andpropylene carbonate.

In some embodiments, the topical compositions comprising atherapeutically effective amount of rofecoxib comprise apharmaceutically acceptable solvent system comprising isosorbidedimethyl ether (DI) and propylene carbonate (PC).

In some embodiments, the topical compositions comprising atherapeutically effective amount of rofecoxib comprise apharmaceutically acceptable solvent system comprising isosorbidedimethyl ether (DI), propylene carbonate (PC), and DMSO.

In some embodiments, the topical compositions comprising atherapeutically effective amount of rofecoxib comprise apharmaceutically acceptable solvent system comprising from about 10% w/wDI to about 20% w/w DI and from about 3% w/w PC to about 8% w/w PC.

In some embodiments, the topical compositions comprising atherapeutically effective amount of rofecoxib comprise apharmaceutically acceptable solvent system comprising about 15% w/w DIand about 5% w/w PC.

In some embodiments, the topical compositions comprising atherapeutically effective amount of rofecoxib comprise apharmaceutically acceptable solvent system comprising DI, PC, and BA.

In some embodiments, the topical compositions comprising atherapeutically effective amount of rofecoxib comprise apharmaceutically acceptable solvent system comprising DI, PC, and DMSO.

In some embodiments, the topical compositions comprising atherapeutically effective amount of rofecoxib comprise apharmaceutically acceptable solvent system comprising DI, PC,

In some embodiments, the topical compositions comprising atherapeutically effective amount of rofecoxib comprise apharmaceutically acceptable solvent system comprising DI, PC, PS20.

In some embodiments, the topical compositions comprise a therapeuticallyeffective amount of rofecoxib comprise a pharmaceutically acceptablesolvent system comprising DI, PC, BA, DMSO, DIA, and PS20.

In some embodiments, the topical compositions comprise a therapeuticallyeffective amount of rofecoxib comprise a pharmaceutically acceptablesolvent system comprising about 15% w/w DI, about 5% w/w PC, about 3%w/w BA, about 20% w/w DMSO, about 12% w/w DIA, and about 15% w/w PS20.

In some embodiments, the topical compositions comprise a therapeuticallyeffective amount of rofecoxib, wherein the therapeutically acceptableamount of rofecoxib is up to 5% w/w.

In some embodiments, the topical compositions described hereincomprising a therapeutically effective amount of rofecoxib and apharmaceutically acceptable solvent system, comprise one or moreadditional ingredients selected from the group consisting of ahumectant, a chelating agent, a UV absorption agent, a moisturizingagent, an excipient, a preservative, a thickening agent, a siliconecontaining compound, an essential oil, a structuring agent, a vitamin, apharmaceutical ingredient, and an antioxidant.

In some embodiments, the topical compositions comprise a therapeuticallyeffective amount of rofecoxib, a pharmaceutically acceptable solventsystem, and oleic acid.

In some embodiments, methods of applying a topical compositioncomprising a therapeutically effective amount of rofecoxib and apharmaceutically acceptable solvent to the skin comprising topicallycomprising the aforementioned composition are provided.

In some embodiments, a method of reducing inflammation, comprisingtopically applying the topical composition comprising a therapeuticallyeffective amount of a topical composition comprising rofecoxib and apharmaceutically acceptable solvent is provided.

In some embodiments, a method of treating arthritis comprising topicallyapplying the topical composition comprising a therapeutically effectiveamount of a topical composition comprising rofecoxib and apharmaceutically acceptable solvent is provided.

In some embodiments, a method of treating acute pain, comprisingtopically applying the topical composition comprising a therapeuticallyeffective amount of a topical composition comprising rofecoxib and apharmaceutically acceptable solvent is provided.

In some embodiments, a method of treating migraines, comprisingtopically applying the topical composition comprising a therapeuticallyeffective amount of a topical composition comprising rofecoxib and apharmaceutically acceptable solvent is provided.

In some embodiments, provided herein is a rofecoxib topical compositionselected from Formulations 1-77, 80, 82, 83, and 85-93.

In some embodiments, provided herein is a rofecoxib topical compositioncomprising Formulation 85.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the calculation of the rofecoxib extinction coefficient.

FIG. 2 shows the solubility of rofecoxib in solvent systems containingone solvent.

FIG. 3 shows the diffusion of Formulation 57 through a Franz cell.

FIG. 4 shows the delivered dose of rofecoxib from rofecoxib topicalcompositions Formulations 80, 82, and 83 as described herein to humanskin over time.

FIG. 5 shows the delivered dose of rofecoxib from rofecoxib topicalcompositions Formulations 80, 82, and 83 to the dermis and epidermis.

FIG. 6 shows the percentage of rofecoxib from rofecoxib topicalcompositions Formulations 80, 82, and 83 delivered to the skin over timeand shows the percentage of rofecoxib delivered to the dermis andepidermis,

FIG. 7 shows the flux of the rofecoxib absorbed through the skin fromthe rofecoxib topical compositions Formulations 80, 82, and 83,

FIG. 8 shows the effect of the rofecoxib topical composition Formulation85 on gait score.

FIG. 9 shows the effect of rofecoxib topical composition Formulation 85on the area under the curve of gait score calculated from 4 hours to 22hours of rats in a rat model of arthritis.

FIG. 10 shows the effect of rofecoxib topical composition Formulation 85on right knee caliper measurement.

FIG. 11 shows the effect of rofecoxib topical composition Formulation 85on the percentage change in right knee caliper measurement frombaseline.

FIG. 12 shows the effect of rofecoxib topical composition Formulation 85on the average right knee caliper change from baseline measured ininches.

FIG. 13 shows the effect of rofecoxib topical composition Formulation 85on the mean area under the curve for knee caliper measurement.

FIG. 14A shows the plasma concentrations of rofecoxib over time afteradministration of oral rofecoxib or topical rofecoxib Formulation 85 ondosing day 1.

FIG. 1.4B shows the plasma concentrations of rofecoxib over time afteradministration of oral rofecoxib or topical rofecoxib Formulation 85 onday 7.

FIG. 15A shows the plasma concentration of 5-OH and the plasmaconcentration of rofecoxib after administration of oral rofecoxib.

FIG. 15B shows the plasma concentration of 5-OH and e plasmaconcentration of rofecoxib after administration of Formulation 85.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the verb “comprise” is used in this description and inthe claims and its conjugations are used in its non-limiting sense tomean that items following the word are included, but items notspecifically mentioned are not excluded.

As used herein, the term “about” refers to plus or minus 10% of thereferenced number unless otherwise stated or otherwise evident by thecontext, and except where such a range would exceed 100% of a possiblevalue, or fall below 0% of a possible value, such as less than 0%content of an ingredient, or more than 100 of the total contents of acomposition. For example, reference to an absolute content of rofecoxibof “about 1% w/w” means that rofecoxib can be present at any amountranging from 0.9% to 1.1% content by weight.

The term “a” or “an” refers to one or more of that entity; for example,“a solvent” refers to one or more solvents or at least one solvent. Assuch, the terms “a” (or “an”), “one or more” and “at least one” are usedinterchangeably herein. In addition, reference to “an element” by theindefinite article “a” or “an” does not exclude the possibility thatmore than one of the elements is present, unless the context clearlyrequires that there is one and only one of the elements.

As used herein, the term “skin” refers to any of the layers of the skin,including the epidermis, dermis, and hypodermis. The epidermis has fivesub-layers, including the stratum corneum, stratum lucidum, stratumgranulosum, stratum spinosum, and stratum basale, which are listed fromthe outermost sub-layer to the innermost sub-layer. For example, thestratum corneum is the skin's surface.

As used herein, the term “topical composition” refers to any formulationthat is applied to the skin.

As used herein, “treat” or “treating” means one or more of relieving,alleviating, delaying, reducing, reversing, improving, or managing atleast one symptom of a condition in a subject. The term “treating” mayalso mean one or more of arresting, delaying the onset (i.e., the periodprior to clinical manifestation of the condition) or reducing the riskof developing or worsening a condition.

Various concentration expressions, including volume concentrations,weight concentrations, and mass concentrations, are utilized to describethe percentage of a component in a solution. Volume concentration hasunits of % v/v, where v/v is volume per volume. If a solution contains5% v/v of a component, 5 of the component is in a total solution of 100mL. Weight concentration of a solution is expressed as % w/w, where w/wis weight per weight. If a solution contains 30% w/w of sodium chloride,the solution contains 30 g of sodium chloride and 70 g of solvent. Massconcentration of a solution is expressed as % w/w, where w/v is weightper volume. If 1 g of sodium chloride is dissolved in a solution with atotal volume of 100 mL, a 1% w/w sodium chloride solution has been made.

As defined herein, “topical application” is application of a compositionto the skin.

As used herein, the term “solvent system” refers to one or more solventsused to solubilize rofecoxib.

As defined herein, the term “pharmaceutically acceptable solvent” refersto a solvent that is not toxic or harmful to a subject.

Topical Compositions Containing Rofecoxib

In some embodiments, the disclosure provides rofecoxib topicalcompositions. Rofecoxib topical compositions contain rofecoxib, asolvent system, and optionally contain additional ingredients and/or avehicle, which are described below. In some embodiments, the rofecoxibtopical compositions are applied topically to the skin. In someembodiments, application of rofecoxib topical compositions alleviateinflammation and/or pain.

Rofecoxib

Rofecoxib is a nonsteroidal anti-inflammatory drug (NSAID). NSAIDs arethe most commonly used drugs in inflammatory diseases. NSAIDS, such asaspirin, ibuprofen, and indomethacin, exert their effects throughinhibition of the COX-1 and COX-2 isoforms of cyclooxygenase. NSAIDSalso are associated with a number of side effects, includinggastrointestinal toxicity, which is primarily dependent on COX-1inhibition. Rofecoxib is a selective inhibitor of cyclooxygenase-2(COX-2). Similar to NSAIDS which inhibit both COX-1 and COX-2, selectiveinhibitors of COX-2 relieve inflammation and pain, but unlike NSAIDSthat inhibit both COX-1 and COX-2, selective inhibitors of COX-2 areassociated with a reduced number of adverse gastrointestinal toxicities.

All NSAIDS inhibit COX-2 to reduce inflammation. Serious adverse eventsof both COX-2 selective (e.g. celecoxib and rofecoxib) and non-selectiveCOX-1 and COX-2 NSAIDS (e.g. ibuprofen, diclofenac, and naproxen) ishypertension and cardiovascular events. COX-2 is responsible for theseserious adverse effects. Because COX-2 regulates the balance of salt inthe kidneys, inhibition of COX-2 can cause hypertension. COX-2 alsocreates prostacyclin which is a blood thinner and lower levels of thiscytokine are associated with cardiovascular events. Therefore, the sideeffects of both selective and non-selective NSAIDs are the same and allhave a similar cardiovascular profile. However, as noted COX-1inhibition causes perforations, ulcers, and bleeds in thegastrointestinal tract, which led to the initiation of COX-2 inhibitordevelopment.

The first long term trials that showed the cardiovascular risk was theAPPROVe trial (Adenomatous Polyp Prevention on Vioxx) by Merck and theAPC (Adenoma Prevention with Celecoxib) trial by Pfizer. As such,although rofecoxib was approved by the Food and Drug Administration(FDA) in 1999 as an oral formulation for the treatment ofosteoarthritis, rheumatoid arthritis, acute pain, primary dysmenorrhea,and migraines, rofecoxib was withdrawn from the market in 2004 by Merckdue to the side effects first conclusively seen in the APPROVe Trial,Pfizer had the same results in its APC trial but left celecoxib on themarket with a Black Box warning. However, all NSAIDs carry the samecardiovascular risks and the FDA has placed a Black Box warning on allNSAIDs including over the counter NSAIDs, e.g., ibuprofen, diclofenacand naproxen. Rofecoxib remains an FDA approved drug listed as“discontinued” in the Orange Book.

In some embodiments, the present disclosure provides topical rofecoxibformulations. In some embodiments, the topical rofecoxib formulations ofthe disclosure reduce the risk of adverse cardiovascular events. In someembodiments, the topical rofecoxib formulations of the disclosure reducethe risk of hypertension. Without being bound by theory, rofecoxibtopical formulations exhibit a reduced effect of adverse cardiovascularevents, because in comparison to oral formulations, rofecoxib topicalformulations result in less systemic absorption of rofecoxib.

In some embodiments, a therapeutically acceptable amount of rofecoxib isincorporated in the topical compositions described herein. As usedherein, a therapeutically acceptable amount is an amount of rofecoxibthat is efficacious, but exhibits fewer side effects than a similar oralcomposition. In some embodiments, the therapeutically acceptable amountof rofecoxib in the compositions of the present disclosure is up to 10%w/w. In some embodiments, the therapeutically acceptable amount ofrofecoxib is up to 5% w/w. In some embodiments, the therapeuticallyacceptable amount of rofecoxib is about 0.1% w/w, about 0.2% w/w, about0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7%w/w, about 0.8% w/w, about 0.9% w/w, about 1.0% w/w, about 1.1% w/w,about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2.0%w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w,about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about2.9% w/w, about 3.0% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3%w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w,about 3.8% w/w, about 3.9% w/w, about 4.0% w/w, about 4.1% w/w, about4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6%w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5.0% w/w,about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9%w/w, about 6.0% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w,about 6.4% w/w, about 6.5% w/w, about 6.5% w/w, about 6.6% w/w, about6.7% w/w, about 6.8% w/w, about 6.9% w/w, about 7.0% w/w, about 7.1%w/w, about 7.2% w/w, about 7.3% w/w, about 7.4% w/w, about 7.5% w/w,about 7.6% w/w, about 7.7% w/w, about 7.8% w/w, about 7.9% w/w, about8.0% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4%w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w,about 8.9% w/w, about 9.0% w/w, about 9.1% w/w, about 9.2% w/w, about9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7%w/w, about 9.8% w/w, about 9.9% w/w, or about 10.0% w/w. In someembodiments, the therapeutically acceptable amount of rofecoxib is about1.0% w/w. In some embodiments, the therapeutically acceptable amount ofrofecoxib is about 2.0% w/w. In some embodiments, the therapeuticallyacceptable amount of rofecoxib is about 3.0% w/w.

Solvent Systems for Dissolving Rofecoxib

In some embodiments, the topical rofecoxib compositions described hereincontain a solvent system. In some embodiments, the solvent system isutilized to solubilize rofecoxib. In some embodiments, rofecoxib is atleast 80% dissolved in the solvent systems described throughout thedisclosure. In some embodiments, rofecoxib is about 80% dissolved, orabout 81% dissolved, or about 82% dissolved, or about 83% dissolved, orabout 84% dissolved, or about 85% dissolved, or about 86% dissolved, orabout 87% dissolved, or about 88% dissolved, or about 89% dissolved, orabout 90% dissolved, or about 91% dissolved, or about 92 dissolved, orabout 93% dissolved, or about 94% dissolved, or about 95% dissolved, orabout 96% dissolved, or about 97 dissolved, or about 98% dissolved, orabout 99% dissolved, or about 100% dissolved when placed in the solventsystem. In some embodiments, rofecoxib is saturated in the solventsystems described herein. In some embodiments, rofecoxib is unsaturatedin the solvent systems described herein. In some embodiments, rofecoxibis supersaturated in the solvent systems described herein.

In some embodiments, the solvent system contains pharmaceuticallyacceptable solvents. In order for a drug, e.g. rofecoxib, to penetrateepithelial tissue upon topical application, the drug must be in solutionin the formulation. The development of a solvent system that solubilizesrofecoxib is difficult, because rofecoxib is insoluble in water and manycommon organic solvents.

Furthermore, an optimal solvent system not only solubilizes rofecoxib,but minimizes the use of potentially toxic solvents. In someembodiments, the solvent systems provided herein for dissolvingrofecoxib follow the International Council for Harmonization ofTechnical Requirements for Pharmaceuticals for Human Use (ICH) guidancefor industry, Q3C Impurities: Residual Solvents, which makesrecommendations as to what amounts of residual solvents are consideredsafe in pharmaceuticals. The Q3C Impurities: Residual Solventsguidelines are incorporated by reference in their entirety herein. U.S.Department of Health and Human Services, Food and Drug Administration,(2017). Q3C Impurities: Residual Solvents.

In some embodiments, the concentration of rofecoxib dissolved in a givensolvent system is used to determine the efficacy of the solvent systemfor solubilizing rofecoxib. In some embodiments, the concentration ofrofecoxib dissolved in solution is identified using methods known to aperson of skill in the art. In some embodiments, the concentration ofrofecoxib is determined using a method selected from the groupconsisting of mass spectrometry, liquid chromatography, ultravioletspectrophotometry, high performance liquid chromatography,ultraviolet-visible (UV-visible) absorption spectroscopy, andimmunoassay. Irk et al. describes the determination of rofecoxibconcentration by ultraviolet spectrophotometry and is incorporated byreference in its entirety herein: Erk et al, Pharmazie. 2004 June;59(6):453-6.

In some embodiments, the solvent systems described herein containsolvents that work through a synergistic effect to dissolve rofecoxib. Asynergistic effect results when the total solubility of rofecoxib in twoor more solvents is greater than the sum of the solubilities ofrofecoxib in the individual solvents. Non-limiting examples of solventsused in the solvent systems described herein include acetone (AC),2-methylpentane-2,4-diol (M24D), alpha-terpineol (AT), benzyl alcohol(BA), diethyl sebacate (DS), diethylene glycol monoethyl ether (DGMF),diisopropyl adipate (DIA), isosorbide dimethyl ether (DI), dimethylsulfoxide (DMSO), ethyl acetate (EA), isopropyl tetradecanoate (IPTD),N-methyl-2-pyrrolidone (MP), oleic acid (OA), polyethylene glycol 400(PEG), polysorbate 20 (PS20), polysorbate 50 (PS80), propylene carbonate(PC), propylene glycol diacetate (PGD), propylene glycol (PPG),acetonitrile, chlorobenzene, chloroform, cyclohexane,1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol,formamide; hexane, methanol, ethanol, 2-methoxyethanol,methylbutylketone, methyl cyclohexane, nitromethane, pyridine,sulfolane, tetraline, toluene, 1,1,2-trichloroethylene, xylene, andlanoline (X). In some embodiments, the solvent system comprises one ormore of 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone,N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,polyvinylpyrrolidone; r-caprolactone and isomers thereof,δ-valerolactone and isomers thereof, β-butyrolactone and isomersthereof, dimethyl isosorbide, isosorbide dimethyl ether, N-methylpyrrolidone, and combinations thereof.

In some embodiments, the solvent system comprises one or more solventscomprising a heterocyclic ring. In some embodiments, the solvent systemcomprises one or more bicyclic solvents. In some embodiments, theheterocyclic ring is a furan, a tetrohydrofuran, a thiophene, pyrrole,pyrrolidine, pyran, piperidine, imidazole, thiazole, dioxane,morpholine, pyrimidine, or a combination thereof. In some embodiments,the solvent system comprises one or more solvents comprising an oxygencontaining heterocycle. In some embodiments, the solvent systemcomprises one or more bicyclic solvents. In some embodiments, a solventwithin a solvent system as described herein is substituted with one ormore functional groups, such as, hydroxyl, ether, aldehyde, ketone,ester, carboxylic acid, amide, or combinations thereof.

In some embodiments, a solvent system described herein comprises one ormore solvents that interrupts or interferes with interactions betweenneighboring rofecoxib molecules. For example, in some embodiments, asolvent system comprises a solvent that disrupts noncovalentinteractions between aromatic rings of rofecoxib, for example, pistacking between individual rofecoxib molecules. In some embodiments, asolvent system comprises a solvent that disrupts pi stacking.Non-limiting examples of solvents that disrupt pi stacking include alphaBisabolol, Alpha Cedrene, Alpha Phellandrene, Alpha Pinene-AlphaTerpineol, Beta, Caryophyllene, Beta Pinene, Borneol, Cadinene,Camphene, Camphor, Caryophyllene Oxide, Citral, Citronellol, Delta 3Carene, Limonene, Eucalyptol, Eugenol, Farnesene, Fenchol, GammaTerpinene, Geraniol, Geranyl Acetate, Humulene, Isoborneol Linalool,Menthol, Myrcene, Nerol Nerolidol, Nookatone, Ocimene, Para-Cymene,Phytol, Quercetin, Terpinolene, and Valencene.

In some embodiments, the solvent systems described herein contain two ormore of the solvents listed throughout this disclosure.

In some embodiments, the solvent system comprises up to about 5% w/w,about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30%w/w; about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, about55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, about 75% w/w,about 80% w/w, about 85% w/w, about 90% w/w, about 95% w/w, or about 99%w/w of the topical rofecoxib compositions.

In some embodiments, the rofecoxib topical composition comprises up toabout 90% w/w of solvent system. In some embodiments, the rofecoxibtopical composition comprises up to about 80% w/w of solvent system. Insome embodiments, the rofecoxib topical composition comprises up toabout 70% w/w of solvent system.

In some embodiments, the rofecoxib topical compositions comprise up toabout 70% w/w of solvent system and up to about 5% w/w rofecoxib. Insome embodiments, the rofecoxib topical compositions comprise up toabout 75% w/w of solvent system and up to about 5% w/w rofecoxib. Insome embodiments, the rofecoxib topical compositions comprise up toabout 80% w/w of solvent system and up to about 5% w/w. In someembodiments, the rofecoxib topical compositions comprise up to about 85%w/w of solvent system and up to about 5% w/w rofecoxib. In someembodiments, the rofecoxib topical compositions comprise up to about 90%w/w of solvent system and up to about 5% w/w rofecoxib. In someembodiments, the rofecoxib topical compositions comprise up to about 95%w/w of solvent system and up to about 5% w/w rofecoxib. In someembodiments, the rofecoxib topical compositions comprise up to about 99%w/w of solvent system and up to about 1% w/w rofecoxib. In someembodiments, the rofecoxib topical compositions comprise up to about 98%w/w of solvent system and up to about 2% w/w rofecoxib. In someembodiments, the rofecoxib topical compositions comprise up to about 95w/w of solvent system and up to about 1% w/w rofecoxib. In someembodiments, the rofecoxib topical compositions comprise up to about 93%w/w of solvent system and up to about 2% w/w rofecoxib. In someembodiments, the rofecoxib topical compositions comprise up to about 97%w/w of solvent system and up to about 2% w/w rofecoxib. In someembodiments, the rofecoxib topical compositions comprise up to about 96%w/w of solvent system and up to about 2% w/w rofecoxib. In someembodiments, the rofecoxib topical compositions comprise up to about 96%w/w of solvent system and up to about 3% w/w rofecoxib.

In some embodiments, a solvent within the solvent systems describedherein comprises from about 0.1% w/w to about 99% w/w of the rofecoxibtopical composition. In some embodiments, a solvent within the solventsystems described herein comprises from about 0.1% w/w, about 0.2% w/w,about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1.0% w/w, about 1.5%w/w, about 2.0% w/w, about 2.5% w/w, about 3.0% w/w, about 3.5% w/w,about 4.0% w/w, about 4.5% w/w, about 5.0% w/w, about 5.5% w/w, about6.0% w/w, about 6.5% w/w, about 7.0% w/w, about 7.5% w/w, about 8.0%w/w, about 8.5% w/w, about 9.0% w/w, about 9.5% w/w, about 10% w/w,about 11% w/w; about 12% w/w; about 13% w/w, about 14% w/w, or about 15%w/w, or about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w,about 20% w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24%w/w, about 25%, about 26% w/w, about 27% w/w, about 28% w/w, about 29%w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w,about 75% w/w, about 80% w/w, about 85% w/w, about 90% w/w, about 95%w/w, or about 99% w/w of the rofecoxib topical composition.

In some embodiments, the solvent systems of the present inventioncomprise mixtures of two or more, three or more, four or more, five ormore, or six or more solvents. The relative amounts of the varioussolvents (as described herein) can vary depending on the specificsolvents used.

In some embodiments, the solvent system contains AC. In someembodiments, the solvent system contains from about 0.1% w/w AC to about15% w/w AC. In some embodiments, the solvent system contains about 1%w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6%w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11%w/w, about 12% w/w, about 13% w/w, about 14% w/w, or about 15% w/w AC,including all values and ranges in between. In some embodiments, therofecoxib topical composition contains from about 0.1% w/w AC to about15% w/w AC. In some embodiments, the rofecoxib topical compositioncontains about 1% w/w; about 2% w/w, about 3% w/w, about 4% w/w; about5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, orabout 15% w/w AC, including all values and ranges in between.

In some embodiments, the solvent system contains M24D. In someembodiments, the solvent system contains from about 0.1% w/w M24D toabout 15% w/w M24D. In some embodiments, the solvent system containsabout 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w,about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w; about 10% w/w,about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, or about 15%w/w M24D, including all values and ranges in between. In someembodiments, the rofecoxib topical composition contains from about 0.1%w/w M24D to about 15% w/w M24D. In some embodiments, the rofecoxibtopical composition contains about 1% w/w, about 2% w/w, about 3% w/w,about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w,about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13%w/w, about 14% w/w, or about 15% w/w M24D, including all values andranges in between.

In some embodiments, the solvent system contains AT. In someembodiments, the solvent system contains from about 0.1% w/w AT to about15% w/w AT. In some embodiments, the solvent system contains about 1%w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6%w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11%w/w, about 12% w/w, about 13% w/w, about 14% w/w, or about 15% AT,including all values and ranges in between. In some embodiments, thesolvent system contains about 5% why AT. In some embodiments, thesolvent system contains about 8% w/w AT. In some embodiments, therofecoxib topical composition contains from about 0.1% w/w AT to about15 w/w AT. In some embodiments, the rofecoxib topical compositioncontains about 5% w/w AT. In some embodiments, the rofecoxib topicalcomposition contains about 8% w/w AT. In some embodiments, the rofecoxibtopical composition contains about 1% w/w, about 2% w/w, about 3% w/w,about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w,about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13%w/w, about 14% w/w, or about 15% w/w AT, including all values and rangesin between.

In some embodiments, the solvent system contains BA. In someembodiments, the solvent system contains from about 0.1% w/w BA to about5% w/w BA. In some embodiments, the solvent system contains about 0.1%w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% WANT, about 0.5% w/w,about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about1.0% w/w, about 1.5% w/w, about 2.0% w/w, about 2.5% w/w; about 3.0%w/w, about 3.5% w/w, about 4.0% w/w, about 4.5% w/w, or about 5.0% w/wBA, including all values and ranges in between. In some embodiments; thesolvent system comprises about 2.5% w/w BA. In some embodiments, thesolvent system comprises about 2.6% w/w BA. In some embodiments, thesolvent system comprises about 2.7% w/w BA. In some embodiments, therofecoxib topical composition contains from about 0.1% w/w BA to about5% w/w BA. In some embodiments, the rofecoxib topical compositioncomprises about 2.5% w/w BA. In some embodiments, rofecoxib topicalcomposition comprises about 2.6% w/w BA. In some embodiments, therofecoxib topical composition comprises about 2.7% w/w BA. In someembodiments, the rofecoxib topical composition contains about 0.1% w/w,about 0.2% w/w, about 0.3% w/w, about 0.4% about 0.5% w/w, about 0.6%w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1.0% w/w,about 1.5% w/w, about 2.0% w/w, about 2.5% w/w, about 3.0% w/w, about3.5% w/w, about 4.0% w/w, about 4.5% w/w, or about 5.0% w/w BA,including all values and ranges in between.

In some embodiments, the solvent system contains DS. In someembodiments, the solvent system contains from about 0.1% w/w DS to about25% w/w DS. In some embodiments, the solvent system contains about 1%w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6%w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11%w/w, about 12% w/w, about 13% w/w, about 14% w/w, or about 15% w/w, orabout 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about 20%w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, orabout 25% w/w DS, including all values and ranges in between. In someembodiments, the rofecoxib topical composition contains from about 0.1%w/w DS to about 25% w/w DS. In some embodiments, the rofecoxib topicalcomposition contains about 1% w/w, about 2% w/w, about 3% w/w, about 4%w/w, about. 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9%w/w, about 10% w/w, about 11% w/w, about 12% w/w about 13% w/w, about14% w/w, or about 15% w/w, or about 16% w/w, about 17% w/w, about 18%w/w, about 19% w/w, about 20% w/w, about 21% w/w, about 22% w/w, about23% w/w, about 24% w/w, or about 25% DS, including all values and rangesin between.

In some embodiments, the solvent system contains DGME. In someembodiments, the solvent system contains from about 0.1% w/w DGMF toabout 50% w/w DGMF. In some embodiments, the solvent system containsabout 0.1% w/w, about 0.5% w/w, 1% w/w, about 2% w/w, about 3% w/w,about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w,about 9% w/w about 10% w/w, about 11% w/w, about 12% w/w, about 13% w/w,about 14% w/w, or about 15% w/w, or about 16% w/w, about 17% w/w, about18% w/w, about 19% w/w, about 20% w/w, about 21% w/w about 22% w/w,about 23% w/w, about 24% w/w, or about 25% w/w, or about 30% w/w, orabout 35% w/w, or about 40% w/w, or about 45% w/w, or about 50% w/wDGMF, including all values and ranges in between. In some embodiments,the solvent system comprises about 18.5% w/w DGME, In some embodiments,the solvent system comprises about 18.2% w/w DGME. In some embodiments,the solvent system comprises about 19% w/w DGME. In some embodiments,the solvent system comprises about 8% w/w DGME. In some embodiments, thesolvent system comprises about 9% w/w DGME. In some embodiments, thesolvent system comprises about 5.4% w/w DGME. In some embodiments, therofecoxib topical composition contains from about 0.1% w/w DGMF to about50% w/w DEME. In some embodiments, the rofecoxib topical compositioncomprises about 19% w/w DGME. In some embodiments, the rofecoxib topicalcomposition comprises about 19.9% w/w DGME. In some embodiments, therofecoxib topical composition comprises about 8% w/w DGME. In someembodiments, the rofecoxib topical composition comprises about 9.1% w/wDGME. In some embodiments, the solvent system comprises about 5.4% w/wDGME. In some embodiments, the rofecoxib topical composition containsabout 0.1% w/w, 0.5% w/w, 1% w/w, about 2% w/w, about 3% w/w; about 4%w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9%w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13 w/w, about14% w/w, or about 15% w/w, or about 16% w/w, about 17% w/w, about 18%w/w; about 19% w/w, about 20% w/w, about 21% w/w, about 22% w/w, about23% w/w, about 24% w/w, or about 25% w/w, or about 30% w/w, or about 35%w/w, or about 40% w/w, or about 45% w/w, or about 50% w/w DGME,including all values and ranges in between.

In some embodiments, the solvent system contains DIA. In someembodiments, the solvent system contains from about 0.1% w/w DIA toabout 15% w/w DIA. In some embodiments, the solvent system containsabout 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w,about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w; about w/w, about11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, or about 15% w/wDIA, including all values and ranges in between. In some embodiments,the solvent system comprises about 10% w/w DIA. In some embodiments, thesolvent system comprises about 11% w/w DIA. In some embodiments, thesolvent system comprises about 12% w/w DIA. In some embodiments, thesolvent system comprises about 13% w/w DIA. In some embodiments, therofecoxib topical composition contains from about 0.1% w/w DR to about15% w/w DIA. In some embodiments, the rofecoxib topical compositioncontains about 1% w/w; about 2% w/w; about 3% w/w, about 4% w/w, about5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w; about10% w/w, about 11% w/w, about 12% w/w; about 13% w/w, about 14% w/w, orabout 15% w/w DIA, including all values and ranges in between. In someembodiments, the rofecoxib topical composition comprises about 10% w/wDIA. In some embodiments, the rofecoxib topical composition comprisesabout 11% w/w DIA. In some embodiments, the rofecoxib topicalcomposition comprises about 12% w/w DIA. In some embodiments, therofecoxib topical composition comprises about 13% w/w DIA.

In some embodiments, the solvent system contains DI. In someembodiments, the solvent system contains from about 0.1% w/w DI to about20% w/w DI. In some embodiments, the solvent system contains about 1%w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6%w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11%w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15% w/w, about16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, or about 20% w/wDI, including all values and ranges in between. In some embodiments, thesolvent system comprises about 15% w/w DI. In some embodiments, thesolvent system comprises about 15.5% w/w DI, In some embodiments, thesolvent system comprises about 16% w/w DI. In some embodiments, therofecoxib topical composition contains from about 0.1% w/w DI to about20% w/w DI. In some embodiments, the rofecoxib topical compositioncontains about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w,about 15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about 19%w/w, or about 20% w/w DI, including all values and ranges in between. Insome embodiments, the rofecoxib topical composition comprises about 15%w/w DI. In some embodiments, the rofecoxib topical composition comprisesabout 15.5% w/w DI. In some embodiments, the rofecoxib topicalcomposition comprises about 16% w/w DI.

In some embodiments, the solvent system contains DMSO. In someembodiments, the solvent system contains from about 0.1% w/w DMSO toabout 50% w/w DMSO. In some embodiments, the solvent system containsabout 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w,about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w,about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, or about 15?A w/w, or about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w,about 20% w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24%w/w, or about 25% w/w, or about 30% w/w, or about 35% w/w, or about 40%w/w, or about 45% w/w, or about 50% w/w DMSO, including all values andranges in between. In some embodiments, the solvent system containsabout 11.5% w/w DMSO, In some embodiments, the solvent system containsabout 16% w/w DMSO. In some embodiments, the solvent system containsabout 21.5% w/w DMSO. In some embodiments, the rofecoxib topicalcomposition contains from about 0.1% w/w DMSO to about 50% w/w DMSO. Insome embodiments, the rofecoxib topical composition contains about 1%w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6%w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11%w/w, about 12% w/w, about 13% w/w, about 14% w/w, or about 15% w/w, orabout 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about 20%w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, orabout 25% w/w, or about 30% w/w, or about 35% w/w, or about 40% w/w, orabout 45% w/w, or about 50% w/w DMSO, including all values and ranges inbetween. In some embodiments, the rofecoxib topical composition containsabout 10% w/w DMSO. In some embodiments, the rofecoxib topicalcomposition contains about 15.5% w/w DMSO. In some embodiments, therofecoxib topical composition contains about 21% w/w DMSO. In someembodiments, the DMSO is 10% DMSO by volume. For example, 10% DMSO maycontain 10 mL of DMSO for 90 mL of water.

In some embodiments, the solvent: system contains EA. In someembodiments, the solvent system contains from about 0.1% w/w EA to about35% w/w EA. In some embodiments, the solvent system contains about 1%w/w, about 2% w/w, about 3% w/w, about 4% w/w, about w/w, about 6% w/w,about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11% w/w,about 12% w/w, about 13% w/w, about 14% w/w, or about 15% w/w, or about16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about 20% w/w,about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, or about 25%w/w, or about 30% w/w; or about 35% w/w EA, including all values andranges in between. In some embodiments, the solvent system containsabout 22.5% w/w EA. In some embodiments, the rofecoxib topicalcomposition contains from about 0.1% w/w EA to about 35% w/w EA. In someembodiments, the rofecoxib topical composition contains about 1% w/w,about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w,about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11% w/w,about 12% w/w, about 13% w/w, about 14% w/w, or about 15% w/w, or about16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about 20% w/w,about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, or about 25%w/w, or about 30% w/w, or about 35% w/w EA, including all values andranges in between. In some embodiments, the rofecoxib topicalcomposition contains about 21.8% w/w EA.

In some embodiments, the solvent system contains IPTD. In someembodiments, the solvent system contains from about 0.1% w/w IPTD toabout 35% w/w IPTD. In some embodiments, the solvent system containsabout 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w,about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w,about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, or about 15%w/w, or about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w,about 20% w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24%w/w, or about 25% w/w, or about 30% w/w, or about 35% w/w IPTD,including all values and ranges in between. In some embodiments, therofecoxib topical composition contains from about 0.1% w/w IPTD to about35% w/w IPTD. In some embodiments, the rofecoxib topical compositioncontains about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, orabout 15% w/w, or about 16% w/w, about 17% w/w, about 18% w/w, about 19%w/w, about 20% w/w, about 21% w/w, about 22% w/w, about 23% w/w, about24% w/w, or about 25% w/w, or about 30% w/w, or about 35% w/w IPTD,including all values and ranges in between.

In some embodiments, the solvent system contains MP. In someembodiments, the solvent system contains from about 0.1% w/w NW to about35% WANT MP, for example about 0.1% w/w MP, about 0.5% w/w, about 1%w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6%w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11%w/w, about 12% w/w, about 13% w/w, about 14% w/w, or about 15% w/w, orabout 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about 20%w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, orabout 25% w/w, or about 30% w/w, or about 35% w/w IPTD, including allvalues and ranges in between.

In some embodiments, the solvent system contains OA. In someembodiments, the solvent system contains from about 0.1% w/w OA to about25% w/w OA. In some embodiments, the solvent system contains about 1%w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11%w/w, about 12% w/w, about 13% w/w, about 14% or about 15% w/w, or about16% WANT, about 17% w/w, about 18% w/w, about 19% w/w, about 20% w/w,about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, or about 25%w/w OA, including all values and ranges in between. In some embodiments,the solvent system comprises about 8% w/w OA. In some embodiments, thesolvent system comprises 5.4% w/w OA. In some embodiments, the rofecoxibtopical composition contains from about 0.1% w/w OA to about 25% w/w OA.In some embodiments, the rofecoxib topical composition contains about 1%w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6%w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11%w/w, about 12% w/w, about 13% w/w, about 14% w/w, or about 15% w/w, orabout 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about 20%w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, orabout 25% w/w OA, including all values and ranges in between. In someembodiments, the rofecoxib topical composition contains about 7.8% w/wOA. In some embodiments, the rofecoxib topical composition containsabout 5.2% w/w OA.

In some embodiments, the solvent system contains PEG. In someembodiments, the solvent system contains from about 0.1% w/w PEG toabout 75% w/w PEG. In some embodiments, the solvent system containsabout 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w,about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w,about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, or about 15%w/w, or about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w,about 20% w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24%w/w, or about 25% w/w, or about 30% w/w, or about 35% w/w, about 40%w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/w, about65% w/w, about 70% w/w, or about 75% w/w PEG, including all values andranges in between. In some embodiments, the rofecoxib topicalcomposition contains from about 0.1% w/w PEG to about 75% w/w PEG. Insome embodiments, the rofecoxib topical composition contains about 1%w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6%w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11%w/w, about 12% w/w, about 13% w/w, about 14% w/w, or about 15% w/w, orabout 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about 20%w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, orabout 25% w/w, or about 30% w/w, or about 35% w/w, about 40% w/w, about45% w/w, about 50% w/w, about 55% w/w, about 60% w/w, about 65% w/w,about 70% w/w, or about 75% w/w PEG, including all values and ranges inbetween.

In some embodiments, the solvent system contains PS20. In someembodiments, the solvent system contains from about 0.1% w/w PS20 toabout 15% w/w PS20. In some embodiments, the solvent system containsabout 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w,about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w; about 10% w/w,about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, or about 15%w/w PS20, including all values and ranges in between. In someembodiments, the solvent system comprises about 15% w/w PS20. In someembodiments, the solvent system comprises about 16% w/w PS20. In someembodiments, the solvent system contains from about 0.1% w/w PS20 toabout 15% w/w PS20. In some embodiments, the solvent system containsabout 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w,about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w; about 10% w/w,about 11% w/w; about 12% w/w, about 13% w/w; about 14% w/w, or about 15%w/w PS20, including all values and ranges in between. In someembodiments, the rofecoxib topical composition comprises about 15% w/wPS20. In some embodiments, the rofecoxib topical composition comprisesabout 16% w/w PS20.

In some embodiments, the solvent system contains PS80. In someembodiments, the solvent system contains from about 0.1% w/w PS80 toabout 15% w/w PS80. In some embodiments, the solvent system containsabout 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w,about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w; about 10% w/w,about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, or about 15%w/w PS80, including all values and ranges in between. In someembodiments, the rofecoxib topical composition contains from about 0.1%w/w PS80 to about 15% w/w PS80. In some embodiments, the rofecoxibtopical composition contains about 1% w/w, about 2% w/w, about 3% w/w,about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w,about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13%w/w, about 14% w/w, or about 15% w/w PS80, including all values andranges in between.

In some embodiments, the solvent system contains PC. In someembodiments, the solvent system contains from about 0.1% tip-/w PC toabout 10% w/w PC. In some embodiments, the solvent system contains about1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6%w/w, about 7% w/w, about 8% w/w, about 9% w/w, or about 10% w/w PC,including all values and ranges in between. In some embodiments, thesolvent system comprises about 5% w/w PC. In some embodiments, thesolvent system comprises about 5.2% w/w PC. In some embodiments, thesolvent system comprises about 5% w/w PC. In some embodiments, therofecoxib topical composition contains from about 0.1% w/w PC to about10% w/w PC. In some embodiments, the rofecoxib topical compositioncontains about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, or about10% w/w PC, including all values and ranges in between. In someembodiments, the rofecoxib topical composition comprises about 5% w/wPC. In some embodiments, the rofecoxib topical composition comprisesabout 5.2% w/w PC. In some embodiments, the rofecoxib topicalcomposition comprises about 5.4% w/w PC.

In some embodiments, the solvent system contains PGD. In someembodiments, the solvent system contains from about 0.1% w/w PGD toabout 15% w/w PGD. In some embodiments, the solvent system containsabout 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w,about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w,about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, or about 15%w/w PGD, including all values and ranges in between, in someembodiments, the solvent system contains about 10.4% w/w PGD. In someembodiments, the rofecoxib topical composition contains from about 0.1%w/w PGD to about 15% % w/w PGD, In some embodiments, the rofecoxibtopical composition contains about 1% w/w, about 2% w/w, about 3% w/w,about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w,about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13%w/w, about 14% w/w, or about 15% w/w PGD, including all values andranges in between. In some embodiments, the rofecoxib topicalcomposition contains about 10.4% w/w PGD.

In some embodiments, the solvent system contains PPG. In someembodiments, the solvent system contains from about 0.1% w/w PPG toabout 95% w/w PPG. In some embodiments, the solvent system containsabout 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w,about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w,about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15%w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/w,about 65% w/w, about 70% w/w, about 75% w/w, about 80% w/w, about 85%w/w, about 90% or about 95% w/w PPG, including all values and ranges inbetween. In some embodiments, the rofecoxib topical composition containsfrom about 0.1% w/w PPG to about 95% w/w PPG. In some embodiments, therofecoxib topical composition contains about 1 w/w, about 2% w/w, about3 w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% www, about 8%w/w, about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about13% w/w, about 14% w/w, about 15% w/w, about 20% w/w, about 25% w/w,about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50%w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, about75% w/w, about 80% w/w, about 85% w/w, about 90% w/w, or about 95% w/wPPG, including all values and ranges in between.

In some embodiments, the solvent system contains lanoline. In someembodiments, the solvent system contains from about 0.1% w/w lanoline toabout 15% w/w lanoline. In some embodiments, the solvent system containsabout 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w,about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w,about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, or about 15%w/w lanoline, including all values and ranges in between.

In some embodiments, the solvent systems described herein contain two ormore solvents that work synergistically to dissolve rofecoxib. In someembodiments, BA and AC work synergistically to dissolve rofecoxib. Insome embodiments, AC and PEG work synergistically to dissolve rofecoxib.In some embodiments, EA and PPG work synergistically to dissolverofecoxib. In some embodiments, PEG and EA work synergistically todissolve rofecoxib. In some embodiments, AC and DGME worksynergistically to dissolve rofecoxib. In some embodiments, AC and PCwork synergistically to dissolve rofecoxib. In some embodiments, AC andDI work synergistically to dissolve rofecoxib. In some embodiments, PCand DI work synergistically to dissolve rofecoxib. In some embodiments,PEG and PGD work synergistically to dissolve rofecoxib. In someembodiments, AC and PGD work synergistically to dissolve rofecoxib. Insome embodiments, DI and PGD work synergistically to dissolve rofecoxib.In some embodiments, PC and PGD work synergistically to dissolverofecoxib. In some embodiments, EA and DMSO work synergistically todissolve rofecoxib. In some embodiments, PEG and PGD worksynergistically to dissolve rofecoxib. In some embodiments, PEG and EAwork synergistically to dissolve rofecoxib. In some embodiments, PEG andMATE work synergistically to dissolve rofecoxib. In some embodiments, EAand DOME work synergistically to dissolve rofecoxib. In someembodiments, EA and BA work synergistically to dissolve rofecoxib. Insome embodiments, DOME and PGD work synergistically to dissolverofecoxib. In some embodiments, AC and PGD work synergistically todissolve rofecoxib. In some embodiments, BA and PGD work synergisticallyto dissolve rofecoxib. In some embodiments, EA and M24D worksynergistically to dissolve rofecoxib.

In some embodiments, solvent systems that contain DI and PC worksynergistically to dissolve rofecoxib. In some embodiments, a solventsystem containing DI and PC contains about 15% w/w DI and about 5% w/wPC. In some embodiments, solvent systems that contain DI and PC and oneor more additional solvents synergistically work to dissolve rofecoxib.In some embodiments, the additional solvents are selected from the groupconsisting of acetone (AC), 2-methylpentane-2,4-diol (M24D),alpha-terpineol (AT), benzyl alcohol (BA), diethyl sebacate (DS),diethylene glycol monoethyl ether (DGME), diisopropyl adipate (DIA),dimethyl sulfoxide (DMSO), ethyl acetate (EA), isopropyltetradecanoate/myristate (IPTD), N-methyl-2-pyrrolidone (MP), oleic acid(OA), polyethylene glycol 400 (PEG), polysorbate 20 (PS20), polysorbate80 (PS80), propylene glycol diacetate (PGD), and propylene glycol (PPG).

In some embodiments, solvent systems that contain DI, PC, and DMSO worksynergistically to dissolve rofecoxib. In some embodiments, a solventsystem containing DI and PC contains about 10-20% DI, 2.5-10% w/w PC,and about 10-20% w/w DMSO. In some embodiments, solvent systemscontaining DI, PC, and DMSO contain about 15% w/w DI and about 5% w/wPC. In some embodiments, solvent systems that contain DI, PC, DMSO andone or more additional solvents synergistically work to dissolverofecoxib. In some embodiments, the additional solvents are selectedfrom the group consisting of acetone (AC), 2-methylpentane-2,4-diol(M24D), alpha-terpineol (AT), benzyl alcohol (BA), diethyl sebacate(DS), diethylene glycol monoethyl ether (DGME), diisopropyl adipatedimethyl sulfoxide (DMSO), ethyl acetate (EA), isopropyltetradecanoate/myristate (IPTD), N-methyl-2-pyrrolidone (MP), oleic acid(OA), polyethylene glycol 400 (PEG), polysorbate 20 (PS20), polysorbate80 (PS80), propylene glycol diacetate (PGD), and propylene glycol (PPG).

In some embodiments, AC, PEG, and PGD work synergistically to dissolverofecoxib. In some embodiments, DI, BA, and PC work synergistically todissolve rofecoxib. In some embodiments, DI, and DMSO worksynergistically to dissolve rofecoxib. In some embodiments, BA, AC, andPEG work synergistically to dissolve rofecoxib. In some embodiments, BA,PEG, and PGD work synergistically to dissolve rofecoxib. In someembodiments, PC, AC, and PGD work synergistically to dissolve rofecoxib.In some embodiments, AC, and PGD work synergistically to dissolverofecoxib. In some embodiments, PC, PEG, and PGD work synergistically todissolve rofecoxib. In some embodiments, DI, PC, and AC, worksynergistically to dissolve rofecoxib. In some embodiments, PC, BA, andAC work synergistically to dissolve rofecoxib. In some embodiments, DI,PC, and BA work synergistically to dissolve rofecoxib. In someembodiments, BA, AC, and PEG work synergistically to dissolve rofecoxib.In some embodiments, PC, AC, and PGD work synergistically to dissolverofecoxib. In some embodiments, DI, PC, and EA work synergistically todissolve rofecoxib. In some embodiments, BA, AC, and PEG worksynergistically to dissolve rofecoxib. In some embodiments, PC, AC, andPEG work synergistically to dissolve rofecoxib. In some embodiments, DI,and DOME work synergistically to dissolve rofecoxib. In someembodiments, DI, PC, and PEG work synergistically to dissolve rofecoxib.In some embodiments, DI, PC, and PGD work synergistically to dissolverofecoxib. In some embodiments, PC, AC, and PGD work synergistically todissolve rofecoxib. In some embodiments, AC, PEG, and PGD worksynergistically to dissolve rofecoxib.

Design of Solvent System for Dissolving Rofecoxib: Solubility Parameters

In some embodiments, solubility parameters may be utilized to select asuitable solvent system for solubilizing rofecoxib. Non-limitingexamples of solubility parameters include the Hildebrand solubilityparameter, the Hansen solubility parameters, and the partitioncoefficient.

In some embodiments, the Hildebrand solubility parameter (5) is utilizedto select a suitable solvent system for solubilizing, rofecoxib. TheHildebrand solubility parameter is defined as the square root of asolvent's cohesive energy density, which is equal to its heat ofvaporization divided by the molar volume. The Hildebrand solubilityparameter is expressed in units of MPa^(1/2). In some embodiments, thesolvent systems described have a. Hildebrand solubility parameter thatis greater than 15.

In some embodiments, the Hansen Solubility Parameters solubilityparameters are utilized to select a suitable solvent system forsolubilizing rofecoxib. The Hansen Solubility Parameters includedispersion (δ_(d)), polar (δ_(d)), and hydrogen bonding (δ_(h))parameters. These three parameters can be treated as coordinates for apoint in a three-dimensional space, which is also known as the Hansenspace. The closest two molecules are in this three-dimensional space,the more likely they are to dissolve into each other. In someembodiments, the Hansen Solubility Parameters teach the skilled artisanabout the intermolecular forces a solvent within the solvent system willmake with other solvents within the solvent system, rofecoxib, or otheradditional ingredients. The Hansen Solubility Parameters are related tothe Hildebrand parameter δ by the formula δ²=δ_(d) ²+δ_(p) ^(2+δ) _(h)². The value for these parameters, for various solvents, can be found inHansen, Charles M Hansen Solubility Parameters, A User's Handbook, CRCPress, 2000, which is incorporated by reference in its entirety herein.In some embodiments, the solvent systems described have a δ_(h) that isgreater than 7. In some embodiments, the solvent systems described havea δ_(d) that is greater than 15. In some embodiments, the solventsystems described have a δ_(p) that is greater than 7. In someembodiments, the solvent systems described have a δ_(h) that is greaterthan 7 and a δ_(d) that is greater than 15. In some embodiments, thesolvent systems described have a δ_(h) that is greater than 7 and aδ_(p) that is greater than 7. In some embodiments, the solvent systemsdescribed have a δ_(d) that is greater than 15 and a δ_(h) that isgreater than 7 and a δ_(p) that is greater than 7. In some embodiments,the solvent systems described have a δ_(h) that is greater than 7, aδ_(d) that is greater than 15, and a δ_(p) that is greater than 7.

In some embodiments, the partition coefficient (P) is used to select asuitable solvent system for solubilizing rofecoxib. The partitioncoefficient describes the propensity of a neutral compound to dissolvein an immiscible biphasic system of lipids and water. In someembodiments, log (P) is utilized to predict whether a compound willdissolve in a given solution. A negative value for logP suggests that acompound will dissolve in an aqueous phase, whereas a positive value forlogP suggests that a compound will dissolve in the lipid phase.

In some embodiments, a solvent systems described herein comprises atleast one solvent with a negative partition coefficient, for example, atleast one solvent, at least two solvents, at least three solvents, atleast four solvents, at least five solvents, or at least six solvents.In some embodiments, solvents having negative partition coefficients mayprovide better transfer across a membrane and/or skin than solventshaving positive partition coefficients. In some embodiments, thepartition coefficient of a solvent within a solvent system describedherein is from about 0.1 to about to about −1.5, about 0 to about −1.5,about −0.001 to about −1.5, about −0.01 to about −1.0, about −0.1 toabout −1.0, and any partition coefficient encompassed by any of theaforementioned ranges.

In some embodiments, a solvent system described herein comprises atleast one solvent with a positive partition coefficient, for example, atleast one solvent, at least two solvents, at least three solvents, atleast four solvents, at least five solvents, or at least six solvents.In some embodiments, a solvent has a partition coefficient from about0.1 to about 2.5, for example, about 0.1 to about 2.5, about 0.1 toabout 1, about 0.1 to about 1.5, about 0.5 to about 1.5, about 1 toabout 2.5, and any partition coefficient encompassed by any one theaforementioned ranges.

In some embodiments, a solvent system comprises at least one solventwith a positive partition coefficient and at least one solvent with anegative partition coefficient. In some embodiments, a solvent systemcomprises at least one solvent with a positive partition coefficient andat least two solvents with a negative partition coefficient. In someembodiments, a solvent system comprises at least two solvents with apositive partition coefficient and at least one solvent with a negativepartition coefficient. In some embodiments, a solvent system comprisesat least two solvents with a positive partition coefficient and at leasttwo solvents with a negative partition coefficient. In some embodiments,a solvent system comprises at least three solvents with a positivepartition coefficient and at least one solvent with a negative partitioncoefficient. In some embodiments, a solvent system comprises at leastone solvent with a positive partition coefficient and at least threesolvents with a negative partition coefficient. In some embodiments, asolvent system comprises at least four solvents with a positivepartition coefficient and at least one solvent with a negative partitioncoefficient. In some embodiments, a solvent system comprises at leastone solvent with a positive partition coefficient and at least foursolvents with a negative partition coefficient. In some embodiments, asolvent system comprises at least four solvents with a positivepartition coefficient and at least two solvents with a negativepartition coefficient. In some embodiments, a solvent system comprisesat least two solvents with a positive partition coefficient and at leastfour solvents with a negative partition coefficient.

In some embodiments, other physical parameters of the solvents disclosedherein, including but not limited to density, the hydrogen bond donorcount, the hydrogen bond acceptor count, heat of vaporization, theenthalpy of fusion, the Kauri-butanol value, aniline cloud-point;heptane number, wax number, aromatic character, and cohesive energydensity are utilized to select a solvent system for the rofecoxibtopical compositions described. Savjani et al. describes many of theseparameters and is incorporated by reference in its entirety herein:Savjani et al. ISRN Pharm. 2012; 2012:195727.

The values of logP, hydrogen bonding donor count (H-Bond D), andhydrogen bonding acceptor count (H-Bond A) for some solvents describedthroughout this disclosure are found in Table 1.

TABLE 1 Solubility Parameters of Solvents H-Bond D, δ Δ_(d) Δ_(p) Δ_(h)Solvent logP H-Bond A (MPa^(1/2)) (MPa^(1/2)) (MPa^(1/2)) (MPa^(1/2))Acetone −0.1 19.9 15.5 10.4 7 2-Methylpentane-2,4- 0.3 2, 2 27.5 16.4 820.6 diol alpha-Terpineol 1.8 1, 1 19.1 17.1 3.6 7.6 95.0+% BenzylAlcohol 1.10 1, 1 23.8 18.4 6.3 13.7 Diethyl Sebacate 3.5 0, 4 17.1 16 44.7 Diethylene Glycol −0.5 1, 3 23.5 16.2 9.2 14.3 Monoethyl EtherDiisopropyl Adipate 2.2 0, 4 Dimethyl Isosorbide −0.6 0, 4 20.4 17.6 7.17.5 Dimethyl Sulfoxide −0.6 0, 2 26.7 18.4 16.4 10.2 Ethyl Acetate 0.760, 2 18.2 15.8 5.3 7.2 Isopropyl 7.2 0, 2 16.8 16.2 2.4 3.7tetradecanoate (also called isopropyl myristate) N-Methyl-2- 0.5 23.0 812.3 7.2 Pyrrolidone Oleic acid 6.5 1, 2 17.4 16 2.8 6.2 PEG 400 4.6 3,1 Polysorbate 20, MP 2.5  3, 10 Polysorbate 80, 4.8  3, 10 AcrosPropylene Carbonate −0.4 0, 3 27.2 20 18 4.1 Propylene Glycol 0.7 2, 2Diacetate Propylene Glycol, −0.9 0, 4 30.2 16.8 9.4 23.3 MP lanoline16.3 19.9 15.5 10.4 7

In some embodiments, the topical rofecoxib compositions provided hereinremain soluble over time. In some embodiments, the topical rofecoxibcompositions provided herein, remain in solution after administration.

Maintenance of Rofecoxib in Solvent System over time

An additional difficulty in formulating rofecoxib topical compositionsis maintaining rofecoxib in solution after application to the skin.Volatility of one or more of the solvents, additional ingredients,and/or vehicle within a topical composition may affect the solubility ofrofecoxib in the rofecoxib topical compositions. Solvent evaporationover time may change the composition of the solvent system.

The penetration rate of rofecoxib, solvents, additional ingredients, andthe vehicle within a topical composition also affects the solubility ofrofecoxib over time. As a topical composition is absorbed by the skin,differential absorption of solvents, additional ingredients, thevehicle, or rofecoxib may change the composition of the rofecoxibtopical composition.

Changes in the composition of the solvent system as a result ofevaporation or differential absorption may lead to precipitation ofrofecoxib solution before penetration of epithelial tissue. Accordingly,the solvent systems used herein to dissolve rofecoxib are not absorbedmore rapidly than the rofecoxib and do not evaporate after application.In some embodiments, the solubility of rofecoxib within the rofecoxibtopical compositions described herein is maintained afteradministration.

In some embodiments, the solubility of rofecoxib is maintained withinthe rofecoxib topical compositions for at least 48 hours afterapplication to the skin. In some embodiments, the solubility ofrofecoxib is maintained within the rofecoxib topical compositions for atleast about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about10 hours, about 11 hours, about 12 hours, about 13 hours, about 14hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours,about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23hours, about 24 hours, about 25 hours, about 26 hours, about 27 hours,about 28 hours, about 29 hours, about 30 hours, about 31 hours, about 32hours, about 33 hours, about 34 hours, about 35 hours, about 36 hours,about 37 hours, about 38 hours, about 39 hours, about 40 hours, about 41hours, about 42 hours, about 43 hours, about 44 hours, about 45 hours,about 46 hours, about 47 hours, or about 48 hours, or more.

In some embodiments, passive diffusion is the mechanism by whichrofecoxib penetrates the skin. Passive diffusion can be describedthermodynamically by Fick's first law:

$J = \frac{{KD}\left( {c_{app} - c_{rec}} \right)}{h}$

where (J) describes the steady state flux per unit area, (K) is thepartition of the drug between the skin and the formulation and (D) isthe diffusion coefficient through the diffusion& path length (h). Sinceusually the concentration of the permeate in the applied dose (c_(app))is so much higher than the concentration in the receptor phase (c_(rec))this equation can be simplified to: J=k_(p)c_(app), where k_(p) is thepermeability coefficient and equal to KD/h (Hadgraft, 2004). Accordingto Fick's law, the most important factors that influence flux across theskin are the concentration gradient of the drug within the skin, thepartition coefficient of the permeate and the diffusion coefficient(Thomas and Finnin, 2004; Hadgraft, 2004), In addition, the flux (J) ofa molecule across a membrane should increase linearly with concentrationuntil c_(pp) reaches the solubility limit i.e. at the point ofsaturation (i.e. a thermodynamic activity (TA) of 1. Assuming there isno interaction between the drug and the vehicle, then this means that,regardless of 1) the nature of the vehicle in the drug saturatedformulation, and 2) the quantity of a drug saturated formulation appliedto the membrane at a TA=1, the flux/release of the drug will remain thesame. Thus, when a saturated drug formulation is applied to the skin,the drug will be at its highest thermodynamic activity, in accordancewith Fick's law.

In some embodiments, rofecoxib is present in a saturating amount in therofecoxib topical compositions described herein. In some embodiments, atleast about 60% of the rofecoxib necessary to achieve saturation ispresent in the rofecoxib topical compositions. In some embodiments, atleast about 60%, about 65%, about 70%, about 75%, about 80%, about 85%,about 90%, about 95%, or about 100% of the rofecoxib necessary toachieve saturation is present in the rofecoxib topical compositions.

In some embodiments, the ability of rofecoxib to penetrate the skin ismeasured. In some embodiments, rofecoxib penetrates the skin when it isdissolved in a solvent system described herein. In some embodiments,rofecoxib is at least about 70% dissolved in the topical rofecoxibcompositions described herein. In some embodiments, rofecoxib is atleast about 70%, about 75%, about 80%, about 85%, about 90%, about 95%,or about 100%; dissolved.

The ability of rofecoxib to penetrate skin is measured according tomethods known by a person of skill in the art. In some embodiments, theability of rofecoxib to penetrate skin is measured using one or moretechniques selected from the group consisting of microscopy, confocalRaman spectroscopy, diffusion cells, static diffusion cells,flow-through cells, tape stripping with high performance liquidchromatography, and skin parallel artificial membrane permeabilityassay. Zsiko et al., which describes many of these methods, isincorporated by reference herein in its entirety (Zsiko et al. Sci.Pharm. 2019, 87(3), 19).

in some embodiments, flux (J) measurements are conducted to evaluate theability of rofecoxib to penetrate the skin. In some embodiments, thefollowing equation is utilized to measure flux (J): J=Q/(A*t), where Qis the quantity of compound traversing the membrane in time t, and A isthe area of exposed membrane in cm². Units of flux are quantity/cm²/min,for example μg/cm²/h or pg/cm²/min, or cpm/cm²/min. Flux measurementsmay be conducted according to known methods in the art. In someembodiments, methods of measuring flux are selected from the groupconsisting of a diffusion cell, a static cell, a continuous flow cell,and fluorescence. The Franz diffusion cell method of measuring flux isdescribed by Ng. et al. and Williams, both of which are incorporated byreference herein in their entirety: Ng et. Al. Pharmaceutics. 2010 June;2(2): 209-223; Williams A C, Transdermal and Topical Drug Delivery:Pharmaceutical Press PhP 2003.

In some embodiments, animal studies will be conducted to evaluate theefficacy of the rofecoxib topical compositions at alleviating painand/or arthritis. Animal studies using conventional pain models,including but not limited to, the formalin model, tail-flick model, hotplate model, complete Freund's Adjuvant (CFA) model, nerve growth factor(NGF) model, Carrageenan Paw Edema (CPE) model, and monoiodoacetate(MIA)-induced osteoarthritis joint pain model. Gregory et al. describesnon-limiting examples of animal models that the rofecoxib topicalcompositions will be evaluated in. Gregory et al. is incorporated byreference herein in its entirety: Gregory et al. J Pain. 2013 November;14(11) In some embodiments, animal models of diseases selected from thegroup consisting of arthritis, osteoarthritis, juvenile rheumatoidarthritis, joint pain due to injury e.g. ankle sprains, sports injuries,carpal tunnel syndrome, ankle sprains, rheumatoid arthritis,inflammation, low back pain, ankylosing spondylitis, psoriaticarthritis, tennis elbow, headache, and migraine will be utilized toevaluate the rofecoxib topical compositions. In some embodiments, therofecoxib topical compositions will be evaluated in humans that exhibitone or more of the following of arthritis, osteoarthritis, juvenilerheumatoid arthritis, joint pain due to injury e.g., ankle sprains,sports injuries, carpal tunnel syndrome, ankle sprains, rheumatoidarthritis, inflammation, low back pain, ankylosing spondylitis,psoriatic arthritis, tennis elbow, headache; and migraine. In someembodiments, the rofecoxib topical compositions will be evaluated inpre-clinical studies as mandated by the Food and Drug Administration fortopical formulations.

Additional Ingredients

In some embodiments, the topical compositions of the present disclosurecan also include any one of, any combination of, or all of the followingadditional ingredients: water, a humectant, a chelating agent, a UVabsorption agent, a moisturizing agent, an excipient, a preservative, athickening agent, a penetration enhancer, a silicone containingcompound, an essential oil, a structuring agent, a vitamin, apharmaceutical ingredient, or an antioxidant, or any combination of suchingredients or mixtures of such ingredients. In certain aspects, thecomposition can include at least two, three, four, five, six, seven,eight, nine, ten, or all of these additional ingredients. U.S. Pat. No.9,814,670 (issued Nov. 14, 2017) describes many of these ingredients andis incorporated by reference in its entirety for all purposes herein.

In some embodiments, about 0.01% w/w to about 40% w/w of an additionalingredient is contained in the topical compositions. In someembodiments, the topical composition contains about 001% w/w about 0.02%w/w, about 0.03% w/w, about 0.04% w/w, about 0.05% w/w, about 0.06% w/w,about 0.07% w/w, about 0.08% w/w, about 0.09% w/w, about 0.10% w/w,about 0.15% w/w, about 0.20% w/w, about 0.25% w/w, about 0.30% w/w,about 0.35% w/w, about 0.40% w/w, about 0.50% w/w, about 0.60% w/w,about 0.70% w/w, about 0.80% w/w, about 0.90% w/w, about 1.0% w/w, about2.0% w/w, about 3.0% w/w, about 4.0% w/w, about 5.0 w/w, about 6.0% w/w,about 7.0% w/w, about 8.0% w/w, about 9.0% w/w, about 10.0% w/w, about11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15% w/w,about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about 20%w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, about25% w/w, about 26% w/w, about 27 w/w, about 28% w/w, about 29% w/w,about 30% w/w, about 31% w/w, about 32% w/w, about 33% w/w, about 34%w/w, about 35% w/w, about 36% w/w, about 37% w/w, about 38% w/w, about39% w/w, or about 40% w/w of additional ingredient.

Humectants

In some embodiments, the present disclosure teaches topical compositionsthat contain a humectant. In some embodiments, humectants causeincreased elasticity, smoothness, and hydration of the skin. In someembodiments, humectants are used in the topical compositions of thedisclosure. Non-limiting examples of humectants include glycerylglucoside, Aloe vera, hyaluronic acid, amino acids, chondroitin sulfate,diglycerol, erythritol, fructose, glucose, glycerol, glycerol polymers,glycol, 1,2,6-hexanetriol, honey, hyaluronic acid, hydrogenated honey,hydrogenated starch hydrolyzate, inositol, lactitol, maltitol, maltose,mannitol, natural humectant factor, PEG-15-butanediol, polyglycerylsorbitol, salts of pyrrolidonecarboxylic acid, potassium PCA, propyleneglycol, saccharide isomerate, sodium glucuronate, sodium PC A, sorbitol,sucrose, trehalose, urea and xylitol,

Chelating Agents

In some embodiments, the compositions of the disclosure containchelating agents. Non-limiting examples of chelating agents includedisodium ethylenediaminetetraacetic acid (EDTA) and tetrasodium EDTA.

UV Absorption Agents

In some embodiments, the compositions of the present disclosure include:UV absorption agents. UV absorption agents include chemical and physicalsunblocks. Non-limiting examples of chemical sunblocks that can be usedinclude para-aminobenzoic acid (PABA), PABA esters (glyceryl PABA,amyldimethyl PABA and octyldimethyl PABA), butyl PABA, ethyl PABA, ethyldihydroxypropyl PABA, benzophenones (oxybenzone, sulisobenzone,benzophenone, and benzophenone-1 through 12), cinnamates (octylmethoxycinnamate, isoamyl p-methoxycinnamate, octylmethoxy cinnamate,cinoxate, diisopropyl methyl cinnamate, DEA-methoxycinnamate, ethyldiisopropylcinnamate, glyceryl octanoate dimethoxycinnamate and ethylmethoxycinnamate), cinnamate esters, salicylates (homomethyl salicylate,benzyl salicylate, glycol salicylate, isopropylbenzyl salicylate, etc.),anthranilates, ethyl urocanate, homosalate, octisalate, dibenzoylmethanederivatives (e.g., avobenzone), octocrylene, octyl triazone, digalloyltrioleate, glyceryl aminobenzoate, lawsone with dihydroxyacetone,ethylhexyl triazone, dioctyl butamido triazone, benzylidene malonatepoly siloxane, terephthalylidene dicamphor sulfonic acid, disodiumphenyl dibenzimidazole tetrasulfonate, diethylamino hydroxybenzoyl hexylbenzoate, bis-diethylamino hydroxybenzoyl benzoate, bisbenzoxazoylphenyl ethylhexylimino-triazine, drometrizole trisiloxane,methylene bis-benzotriazolyl tetramethylbutylphenol, andbis-ethylhexyloxyphenol methoxyphenyltriazine, 4-methylbenzylidenecamphor, and isopentyl-4-methoxycinnamate. Non-limiting examples ofphysical sunblocks include, kaolin, talc, petrolatum and metal oxides(e.g., titanium dioxide and zinc oxide).

Emollients

In some embodiments, the compositions of the disclosure contain one ormore emollients. Emollients are lubricating ingredients that make theskin soft and smooth and help the skin to retain moisture. Non-limitingexamples of emollients include vegetable oils, mineral oils, rheabutter, cocoa butter, petrolatum, cholesterol, silicone, and animal oils(including emu, mink, and lanolin).

Moisturizing Agent

In some embodiments, the compositions of the disclosure containmoisturizing agents. Non-limiting examples of moisturizing agents thatcan be used with the compositions of the present invention include aminoacids, chondroitin sulfate; diglycerin, erythritol, fructose, glucose,glycerin, glycerol polymers, glycol, 1,2,6-hexanetriol, honey,hyaluronic acid, hydrogenated honey, hydrogenated starch hydrolysate,inositol, lactitol, maltitol, maltose, mannitol, natural moisturizingfactor, PEG-15 butanediol, polyglyceryl sorbitol, salts of pyrrolidonecarboxylic acid, potassium PCA, propylene glycol, sodium glucuronate,sodium PCA, sorbitol, sucrose, trehalose, urea, and xylitol.

Other examples include acetylated lanolin, acetylated lanolin alcohol,alanine, algae extract, aloe barbadensis, aloe-barbadensis extract, aloebarbadensis gel, althea officinalis extract, apricot (prunus armeniaca)kernel oil, arginine, arginine aspartate, arnica moniana extract,aspartic acid, avocado (persea gratissima) oil, barrier sphingolipids,butyl alcohol, beeswax, behenyl alcohol, beta-sitosterol, birch (betulaalba) bark extract, borage (borage officinalis) extract, butcherbroom(ruscus aculeatus) extract, butylene glycol, Calendula officinalisextract, Calendula officinalis oil, candelilla (euphordia cerifera) wax,canola caprylic/capric triglyceride, cardamom (Elettaria cardamomum)oil, carnauba (Copernicia cenifera) wax, carrot (Dancus carota sativa)oil, castor (Ricinus communis) oil, ceramides, ceresin, ceteareth-5,ceteareth-12, ceteareth-20, cetearyl octanoate, ceteth-20, ceteth-24,cetyl acetate, cetyl octanoate, cetyl palmitate, chamomile (anthemisnobilis) oil, cholesterol, cholesterol esters, cholesterylhydroxystearate, citric acid, clary (salvia sclarea) oil, cocoa(Theobroma cacao) butter, coco-caprylate/caprate, coconut (cocasnucifera) oil, collagen, collagen amino acids, corn (Zea mays) oil,fatty acids, decyl oleate, dimethicone copolyol, dimethiconol, dioctyladipate, dioctyl succinate, dipentaerythrityl hexacaprylate/hexacaprate,DNA, erythritol, ethoxydiglycol, ethyl linoleate, eucalyptus globulusoil, evening primrose (Oenothera biennis) oil, fatty acids, geraniummaculatum oil, glucosamine, glucose glutamate, glutamic acid,glycereth-26, glycerin, glycerol, glyceryl distearate, glycerylhydroxystearate, glyceryl laurate, glyceryl linoleate, glycerylmyristate, glyceryl oleate, glyceryl stearate, glyceryl stearate SE,glycine, glycol stearate, glycol stearate SE, glycosaminoglycans, grape(Vitis vinifera) seed oil, hazel (Corylus americana) nut oil, hazel(Corylus avellana) nut oil, hexylene glycol, hyaluronic acid, hybridsafflower (Carthamus tinctorius) oil, hydrogenated castor oil,hydrogenated coco-glycerides, hydrogenated coconut oil, hydrogenatedlanolin, hydrogenated lecithin, hydrogenated palm glyceride,hydrogenated palm kernel oil, hydrogenated soybean oil, hydrogenatedtallow glyceride, hydrogenated vegetable oil, hydrolyzed collagen,hydrolyzed elastin, hydrolyzed glycosaminoglycans, hydrolyzed keratin,hydrolyzed soy protein, hydroxylated lanolin, hydroxyproline, isocetylstearate, isocetyl stearoyl stearate, isodecyl oleate, isopropylisostearate, isopropyl lanolate, isopropyl myristate, isopropylpalmitate, isopropyl stearate, isostearamide DEA, isostearic acid,isostearyl lactate, isostearyl neopentanoate, jasmine (Jasminumofficinale) oil, jojoba (Buxus chinensis) oil, kelp, kukui (Aleuritesmoluccana) nut oil, lactamide MEA, laneth-16, laneth-10 acetate,lanolin, lanolin acid, lanolin alcohol, lanolin oil, lanolin wax,lavender (Lavandula augustifolia) oil, lecithin, lemon (Citrus Medicalimonum) oil, linoleic acid, linolenic acid, macadamia ternifolia nutoil, maltitol, matricaria (chamomilla recutita) oil, methyl glucosesesquistearate, methylsilanol PCA, mineral oil, mink oil, mortierellaoil, myristyl lactate, myristyl myristate, myristyl propionate,neopentyl glycol dicaprylate/dicaprate, octyldodecanol, octyldodecylmyristate, octyldodecyl stearoyl stearate, octyl hydroxystearate, octylpalmitate, octyl salicylate, octyl stearate, oleic acid, olive (Oleaeuropaea) oil, orange (Citrus aurantium dulcis) oil, palm (Elaeisguineensis) oil, palmitic acid, pantethine, panthenol, panthenyl ethylether, paraffin, PCA, peach (Prunus persica) kernel oil, peanut (Arachishypogaea) oil, PEG-8 C12-18 ester. PEG-15 cocamine, PEG-150 distearate,PEG-60 glyceryl isostearate, PEG-5 glyceryl stearate, PEG-30 glycerylstearate, PEG-7 hydrogenated castor oil, PEG-40 hydrogenated castor oil,PEG-60 hydrogenated castor oil, PEG-20 methyl glucose sesquistearate,PEG-40 sorbitan peroleate, PEG-5 soy sterol, PEG-10 soy sterol, PEG-2stearate, PEG-8 stearate, PEG-20 stearate, PEG-32 stearate, PEG-40stearate, PEG-50 stearate, PEG-100 stearate, PEG-150 stearate,pentadecalactone, peppermint (Mentha piperita) oil, petrolatum,phospholipids, poly amino sugar condensate, polyglyceryl-3diisostearate, polyquaternium-24, polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 80, polysorbate 85, potassium myristate,potassium palmitate, propylene glycol, propylene glycoldicaprylate/dicaprate, propylene glycol dioctanoate, propylene glycoldipelargonate, propylene glycol laurate, propylene glycol stearate,propylene glycol stearate SE, PVP, pyridoxine dipalmitate, retinol,retinol palmitate, rice (Oryza sativa) bran oil. RNA, rosemary(Rosmarinus officinalis) oil, rose oil, safflower (Carthamus tinctorius)oil, sage (Salvia officinalis) oil, sandalwood (santaltan album) oil,serine, serum protein, sesame (Sesamum indicum) oil, rhea butter(Butyrospermum parkii), silk powder, sodium chondroitin sulfate, sodiumhyaluronate, sodium lactate, sodium palmitate, sodium PCA, sodiumpolyglutamate, soluble collagen, sorbitan laurate, sorbitan oleate,sorbitan palmitate, sorbitan sesquioleate, sorbitan stearate, sorbitol,soybean (glycine soja) oil, sphingolipids, squalane, squalene,stearamide MEA-stearate, stearic acid, stearoxy dimethicone,stearoxytrimethylsilane, stearyl alcohol, stearyl glycyrrhetinate,stearyl heptanoate, stearyl stearate, sunflower (Helianthus annuus) seedoil, sweet almond (prunes Amygdalus dulcis) oil, synthetic beeswax,tocopherol, tocopheryl acetate, tocopheryl linoleate, tribehenin,tridecyl neopentanoate, tridecyl stearate, triethanolamine, tristearin,urea, vegetable oil, water, waxes, wheat (Triticum vulgare) germ oil,and ylang ylang (Cananga odorata) oil.

Preservatives

In some embodiments, the compositions of the disclosure containpreservatives. Non-limiting examples of preservatives include quaternaryammonium preservatives such as polyquaternium-1 and benzalkonium halides(e.g., benzalkonium chloride (“BAC”) and benzalkonium bromide), parabens(e.g., methylparabens and propylparabens), phenoxyethanol, benzylalcohol, chlorobutanol, phenol, sorbic acid and salts thereof,thimerosal, potassium sorbate, or combinations thereof. In someembodiments, paraben is not included in the formulations of thedisclosure.

Thickening Agents

in some embodiments, the compositions of the disclosure containthickening agents. Thickening agents, including thickener or gellingagents, include substances which that can increase the viscosity of acomposition. Thickeners includes those that can increase the viscosityof a composition without substantially modifying the efficacy of theactive ingredient within the composition. Thickeners can also increasethe stability of the compositions of the present invention. In certainaspects of the present invention, thickeners include hydrogenatedpolyisobutene, ttihydroxystearin, ammonium acryloyldimethyltaurate/vpcopolymer, or a mixture thereof.

Non-limiting examples of additional thickening agents that can be usedin the context of the present invention include carboxylic acidpolymers, cross-linked polyacrylate polymers, polyacrylamide polymers,polysaccharides, and gums. Examples of carboxylic acid polymers includecross-linked compounds containing one or more monomers derived fromacrylic acid, substituted acrylic acids, and salts and esters of theseacrylic acids and the substituted acrylic acids, wherein thecrosslinking agent contains two or more carbon-carbon double bonds andis derived from a polyhydric alcohol (see U.S. Pat. Nos. 5,087,445;4,509,949; 2,798,053; CTFA International Cosmetic Ingredient Dictionary,Fourth edition, 1991, pp. 12 and 80). Examples of commercially availablecarboxylic acid polymers include carbomers, which are homopolymers ofacrylic acid cross-linked with allyl ethers of sucrose orpentaerythritol (e.g., Carbopol™ 900 series from B. F. Goodrich).

Non-limiting examples of cross-linked polyacrylate polymers includecationic and nonionic polymers. Examples are described in U.S. Pat. Nos.5,100,660; 4,849,484; 4,835,206; 4,628,078; 4,599,379, each of which isincorporated by reference in its entirety for all purposes herein.

Non-limiting examples of polyacrylamide polymers (including nonionicpolyacrylamide polymers including substituted branched or unbranchedpolymers) include polyacrylamide, iso-paraffin and laureth-7,multi-block copolymers of acrylamides and substituted acrylamides withacrylic acids and substituted acrylic acids.

Non-limiting examples of polysaccharides include cellulose,carboxymethyl hydroxyethylcellulose, cellulose acetate propionatecarboxylate, hydroxyethylcellulose, hydroxyethyl ethyl cellulose,hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose, methylhydroxyethylcellulose, microcrystalline cellulose, sodium cellulosesulfate, and mixtures thereof. Another example is an alkyl substitutedcellulose where the hydroxy groups of the cellulose polymer ishydroxyalkylated (preferably hydroxy ethylated or hydroxypropylated) toform a hydroxyalkylated cellulose which is then further modified with aC10-C30 straight chain or branched chain alkyl group through an etherlinkage. Typically these polymers are ethers of C10-C30 straight orbranched chain alcohols with hydroxyalkylcelluloses. Other usefulpolysaccharides include scleroglucans comprising a linear chain of (1-3)linked glucose units with a (1-6) linked glucose every three unit. Insome embodiments, cellulose is used as a thickener. In some embodiments,hydroxypropylcellulose (HPC) is used as a thickener. In someembodiments, hydroxypropylcellulose has an average molecular weight of100,000 g/mol. In some embodiments, the topical rofecoxib compositionscomprise between about 1% w/w and about 10% w/w HPC, for example, about1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6%w/w, about 7% w/w, about 8% w/w, about 9% w/w, or about 10% w/w HPC, Insome embodiments, the topical rofecoxib compositions comprise about 4%w/w HPC. In some embodiments, the rofecoxib topical compositionscomprise about 3% w/w HPC.

In some embodiments, PS20 is used as a thickener in the rofecoxibtopical composition. In some embodiments, PS80 is used as a thickener inthe rofecoxib topical compositions. In some embodiments, PEG is used asa thickener in the rofecoxib topical compositions.

Non-limiting examples of gums that can be used with the presentinvention include acacia, agar, algin, alginic acid, ammonium alginate,amylopectin, calcium alginate, calcium carrageenan, carnitine,carrageenan, dextrin, gelatin, gellan gum, guar gum, guarhydroxypropyltrimonium chloride, hectorite, hyaluronic acid, hydratedsilica, hydroxypropyl chitosan, hydroxypropyl guar, karaya gum, kelp,locust bean gum, natto gum, potassium alginate, potassium carrageenan,propylene glycol alginate, sclerotium gum, sodium carboxymethyl dextran,sodium carrageenan, tragacanth gum, xanthan gum, and mixtures thereof.In some embodiments, xanthan gum is added to the rofecoxib topicalcompositions as a thickener.

Silicone Containing Compounds

In some embodiments, the compositions of the disclosure contain asilicone containing compound. In non-limiting aspects, siliconecontaining compounds include any member of a family of polymericproducts whose molecular backbone is made up of alternating silicon andoxygen atoms with side groups attached to the silicon atoms. By varyingthe —Si—O— chain lengths, side groups, and crosslinking, silicones canbe synthesized into a wide variety of materials. They can vary inconsistency from liquid to gel to solids.

The silicone containing compounds that can be used in the context of thepresent disclosure include those described in this specification orthose known to a person of ordinary skill in the art. Non-limitingexamples include silicone oils (e.g., volatile and non-volatile oils),gels, and solids. In certain aspects, the silicon containing compoundsincludes a silicone oils such as a polyorganosiloxane. Non-limitingexamples of polyorganosiloxanes include dimethicone, cyclomethicone,polysilicone-11, phenyl trimethicone, trimethylsilylamodimethicone,stearoxytrimethylsilane, or mixtures of these and other organosiloxanematerials in any given ratio in order to achieve the desired consistencyand application characteristics depending upon the intended application(e.g., to a particular area such as the skin, hair, or eyes). A“volatile silicone oil” includes a silicone oil have a low heat ofvaporization, i.e., normally less than about 50 cal per gram of siliconeoil. Non-limiting examples of volatile silicone oils include:cyclomethicones such as Dow Corning 344 Fluid, Dow Corning 345 Fluid,Dow Corning 244 Fluid, and Dow Corning 245 Fluid, Volatile Silicon 7207(Union Carbide Corp., Danbury, Conn.); low viscosity dimethicones, i.e.dimethicones having a viscosity of about 50 cst or less (e.g.,dimethicones such as Dow Corning 200-0.5 cst Fluid). The Dow CorningFluids are available from Dow Corning Corporation, Midland, Mich.Cyclomethicone and dimethicone are described in the Third. Edition ofthe CTFA Cosmetic Ingredient Dictionary (incorporated by reference) ascyclic dimethyl polysiloxane compounds and a mixture of fully methylatedlinear siloxane polymers end-blocked with trimethylsiloxy units,respectively. Other non-limiting volatile silicone oils that can be usedin the context of the present disclosure include those available fromGeneral Electric Co., Silicone Products Div., Waterford, N.Y. and SWSSilicones Div. of Stauffer Chemical Co., Adrian, Mich.

Essential Oils

In some embodiments, the compositions of the disclosure containessential oils. Essential oils include oils derived from herbs, flowers,trees, and other plants. Such oils are typically present as tinydroplets between the plant's cells, and can be extracted by severalmethod known to those of skill in the art (e.g., steam distilled,enfleurage (extraction by using fat), maceration, solvent extraction, ormechanical pressing). When these types of oils are exposed to air theytend to evaporate (i.e., a volatile oil). As a result, many essentialoils are colorless, but with age they can oxidize and become darker.Essential oils are insoluble in water and are soluble in alcohol, ether,fixed oils (vegetal), and other organic solvents. Typical physicalcharacteristics found in essential oils include boiling points that varyfrom about 160° C. to 240° C. and densities ranging from about 0.759g/ml, to about 1.096 g/mL.

Essential oils typically are named by the plant from which the oil isfound. For example, rose oil or peppermint oil are derived from rose orpeppermint plants, respectively. Non-limiting examples of essential oilsthat can be used in the context of the present invention include sesameoil, macadamia nut oil, tea tree oil, evening primrose oil, Spanish sageoil, Spanish rosemary oil, coriander oil, thyme oil, pimento berriesoil, rose oil, anise oil, balsam oil, bergamot oil, rosewood oil, cedaroil, chamomile oil, sage oil, clary sage oil, clove oil, cypress oil,eucalyptus oil, fennel oil, sea fennel oil, frankincense oil, geraniumoil, ginger oil, grapefruit oil, jasmine oil, juniper oil, lavender oil,lemon oil, lemongrass oil, lime oil, mandarin oil, marjoram oil, myrrhoil, neroli oil, orange oil, patchouli oil, pepper oil, black pepperoil, petitgrain oil, pine oil, rose otto oil, rosemary oil, sandalwoodoil, spearmint oil, spikenard oil, vetiver oil, wintergreen oil, orylang ylang. In some embodiments, the topical compositions comprisespearmint oil. In some embodiments, the topical compositions compriseeucalyptus oil.

In some embodiments, the topical compositions described herein comprisebetween about 0.1% w/w and about 2% w/w, for example, about 0.1% w/w,about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w,about 1.1% w/w, about 1.2 w/w, about 1.3% w/w, about 1.4 w/w, about 1.5%w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, orabout 2.0% WAV of essential oils. In some embodiments, the topicalcompositions described herein comprise about 1% w/w essential oils. Insome embodiments, the topical compositions described herein compriseabout 0.33% w/w spearmint oil. In some embodiments, the topicalcompositions described herein comprise about 0.67% w/w spearmint oil. Insome embodiments, the topical compositions described herein compriseabout 0.33% w/w eucalyptus oil. In some embodiments, the topicalcompositions described herein comprise about 0.67% w/w eucalyptus oil.

Other essential oils known to those of skill in the art are alsocontemplated as being useful within the context of the presentinvention.

Carrier Oils

In some embodiments, the compositions of the disclosure contain carrieroils. Carrier oils are used to dilute essential oils so they can beapplied to the skin without side effects. Non-limiting examples ofcarrier oils include coconut oil (Cocas nucifera), black cumin seed oil(Nigella sativa), jojoba oil (Simmondsia chinensis), evening primroseoil Oenothera biennis), rose hip oil (Rosa mosqueta), aloe (Aloe vera),and grapeseed oil (Vitus vinifera). In some embodiments, Aloe vera isused as a carrier oil.

Structuring Agents

In some embodiments, the compositions of the disclosure containstructuring agents. Structuring agents, in certain aspects, assist inproviding rheological characteristics, which contribute to thecomposition's stability. In other aspects, structuring agents can alsofunction as an emulsifier or surfactant. Non-limiting examples ofstructuring agents include stead c acid, palmitic acid, stearyl alcohol,cetyl alcohol, behenyl alcohol, stearic acid, palmitic acid, thepolyethylene glycol ether of stearyl alcohol having an average of about1 to about 21 ethylene oxide units, the polyethylene glycol ether ofcetyl alcohol having an average of about 1 to about 5 ethylene oxideunits, and mixtures thereof.

Vitamins and Minerals

In some embodiments, the compositions of the disclosure contain one ormore vitamins, minerals, or amino acids. Non-limiting examples ofvitamins include vitamin A, ascorbic acid (vitamin C), vitamin D,vitamin E, vitamin K, thiamine, riboflavin, niacin, pantothenic acid,pyridoxine, biotin, folate, cobalamin, and cyanocobalamin. Non-limitingexamples of minerals that can be included in the compositions of thepresent invention include antimony, barium, beryllium, bismuth, boron,bromine, calcium, carbon, cerium, cesium, chloride, chromium, cobalt,copper, dysprosium, erbium, europium, fluorine, gadolinium, gallium,germanium, gold, hafnium, holmium, indium, iodine, iridium, iron,lanthanum, lithium, magnesium, manganese, molybdenum, neodymium, nickel,niobium, osmium, palladium phosphorus, platinum, potassium,praesodymium, rhenium, rhodium, rubidium, ruthenium, samarium, sodium,selenium, silicon, silver, sodium, strontium, sulfur, tantalum,thallium, thorium, tellurium, terbium, thulium, tin, titanium, tungsten,ytterbium, yttrium, zinc, and zirconium. Any soluble salt of theseminerals suitable for inclusion edible products can be used, forexample, calcium carbonate, calcium citrate, calcium malate,calcium-citrate-malate, calcium gluconate, magnesium citrate, magnesiumgluconate, magnesium sulfate, zinc chloride; zinc sulfate, potassiumiodide, and copper sulfate.

In some embodiments, the compositions of the disclosure include aminoacids. Non-limiting examples of amino acids include alanine, glutamicacid, glycine, histidine, isoleucine, leucine, methionine,phenylalanine, serine, threonine, tryptophan, valine, aspartic acid,arginine, asparagine, glutamine, proline, cysteine, and lysine.

In some embodiments, the minerals and amino acids are contained within aproduct, which is incorporated into the compositions of the disclosure.

Pharmaceutical Ingredients

In some embodiments, the compositions of the disclosure containpharmaceutical ingredients. Non-limiting examples of pharmaceuticalactive agents include anti-acne agents, agents used to treat rosacea,analgesics, anesthetics, anorectals, antihistamines, anti-inflammatoryagents including non-steroidal anti-inflammatory drugs, antibiotics,antifungals, antivirals, antimicrobials, anti-cancer actives,scabicides, pediculicides, antineoplastics, antiperspirants,antipruritics, antipsoriatic agents, antiseborrheic agents, biologicallyactive proteins and peptides, burn treatment agents, cauterizing agents,depigmenting agents, depilatories, diaper rash treatment agents,enzymes, hair growth stimulants; hair growth retardants includingdifluoromethylornithine (DFMO) and its salts and analogs, hemostatics,kerotolytics, canker sore treatment agents, cold sore treatment agents,dental and periodontal treatment agents, photosensitizing actives, skinprotectant/barrier agents, steroids including hormones andcorticosteroids, sunburn treatment agents, sunscreens, transdermalactives, nasal actives, vaginal actives, wart treatment agents, woundtreatment agents, and wound healing agents. In some embodiments,methyl-4-Hydroxybenzoate is added to the rofecoxib topical compositions.In some embodiments, methyl-4-Hydroxybenzoate is an anti-fungal.

In some embodiments, the pharmaceutical ingredient is a steroid.Non-limiting examples of steroids include dexamethasone; dexamethasoneacetate; dexamethasone sodium phosphate, cortisone, cortisone acetate,hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, sodiumhydrocortisone phosphate, prednisol hydrochloroneone acetate, prednisolacetate Prednisolone, Prednisolone Sodium Phosphate, PrednisoloneTebutate, Prednisolone Pivalate, Triamcinolone, Triamcinolone Acetonide,Triamcinolone Hexacetonide, Triamcinolone Diacetate, MethylprednisoloneMethylprednisolone Acetate, Sodium Methodotassium Sodium Methionate,Sodium Methionate Diploate betamethasone, betamethasone, disodiumphosphate of vetamethasone, sodium phosphate of vetamethasone,betamethasone acetate, disodium phosphate of betamethasone,chloroprednisone acetate, corticosterone, deoxycorticosterone,deoxycorticosterone acetate, deoxymethyrostaone deoxyketol ester,fludrocortisone, fludrocortisone acetate, dichlorisone acetate,fluorohydrocortisone, fluorometolone, fluprednisolone, parametasona,parametasona acetate, androsterone, fluoxymesterone, aldosterone,methandrostenolone, methyrostenedione, methyldostentaone testosterone,testosterone testosterone, testosterone equonates testosterone,estradiol benzoate, estradiol dipropionate, estriol, estrone, estronebenzoate, acetoxypregnenolone, anagestone acetate, chlormadinoneacetate, flurogestone acetate, hydroxymethylprogesterone,hydroxymethylprogesterone acetate, hydroxyprogesterone,hydroxyprogesterone hydroxyprogesterone, hydroxyprogesterone acetate,nomethisterone, pregnenolone, progesterone, ethinyl estradiol,mestranol, dimethisterone, etisterone, ethinodiol diacetate,norethindrone, norethindrone acetate, norethisterone, fluocinoloneacetonide, flurandrenolone, succinate hydrocortisone succinate,methylprednisolone sodium, prednisolone sodium phosphate, triamcinoloneacetonide, sodium hydroxydione, spironolactone, oxandrolone,oxymetholone, prometholone, testosterone cypionate, testosteronephenylacetate, estradiol cypionate and noretynodrel

Excipients

In some embodiments, the compositions of the disclosure containexcipients. In some embodiments, the topical composition contains one ormore excipients selected from the list consisting of alpha-tocopherol,1,2,6-hexanetriol,6-methoxy-2-(4-styryl-3-sulfophenol)-2-h-benzotriazole, acetic acid,acetyltributyl citrate, acrylates copolymer, adhesive tape, alcloxa,alcohol, algeldrate, alkyl aryl sodium sulfonate, allantoin, almond oil,aloe, alpha-terpineol, aluminum acetate, aluminum hydroxide, aluminummonostearate, aluminum oxide, aluminum polyester, aluminum silicate,aluminum starch octenylsuccinate, aluminum stearate, aluminum sulfateanhydrous, amaranth, amerchol cab, aminomethylpropanol, ammoniasolution, ammonium lauryl sulfate, amphoteric-9, anhydrous citric acid,anhydrous dibasic calcium phosphate, anhydrous trisodium citrate, anoxidsbn, apricot kernel oil peg-6 esters, aquaphor, arlacel, ascorbic acid,ascorbyl palmitate, aseptoform m, beeswax, synthetic, bentonite,benzalkonium chloride, benzethonium chloride, benzocaine, benzoic acid,benzoin resin, benzyl alcohol, beta carotene, betadex, boric acid,butane, butyl alcohol, butyl ester of methyl vinyl ether/maleicanhydride copolymer (125000 mw), butyl methacrylate and methylmethacrylate copolymer (3:1; 150000 mw), butyl stearate, butylatedhydroxyanisole, butylated hydroxytoluene, butylene glycol, butylparaben,c13-14 isoparaffin/laureth-7/polyacrylamide, calcium acetate, canadabalsam, captan, caramel, carbomer 1382, carbomer copolymer type a (allylpentaerythritol crosslinked), carbomer copolymer type b pentaerythritolcrosslinked), carbomer homopolymer type a (allyl pentaerythritolcrosslinked), carbomer homopolymer type b (allyl pentaerythritolcrosslinked), carbomer homopolymer type b (allyl sucrose crosslinked),carbomer homopolymer type c (allyl pentaerythritol crosslinked),carboxymethylcellulose, carboxymethylcellulose sodium,carboxypolymethylene, carnauba wax, carrageenan, carrageenan sodium,castile soap, castor oil, ceteareth-12; ceteareth-15, ceteareth-30,cetearyl alcohol/ceteareth-20, cetearyl ethylhexanoate, ceteth-10,ceteth-2, ceteth-20, ceteth-23, cetostearyl alcohol, cetyl alcohol,cetyl esters wax, cetyl palmitate, chlorobutanol, chlorobutanolhemihydrate, chlorocresol, chloroxylenol, cholesterol, choleth-24,chondrus crispus, citric acid monohydrate, coco diethanolamide, cocomonoethanolamide, coco-betaine, coconut acid, coconut oil, cocoylcaprylocaprate, cold cream, collagen, copovidone k25-31, corn oil,crospovidone, cyclomethicone, cyclomethicone 5,cyclomethicone/dimethicone copolyol, d&c green no. 5, d&c red no: 28,d&c red no. 33, d&c yellow no. 10, d&c yellow no. 10-aluminum lake,dehydag wax sx, dehydroacetic acid, dehymuls e, denatonium benzoate,diatomaceous earth, diazolidinyl urea, dichlorobenzyl alcohol,dichlorodifluoromethane; dichlorotetrafluoroethane; diethanolamine;diethyl sebacate; diethylene glycol monoethyl ether, dihydroxy aluminumaminoacetate, diisopropanolamine, diisopropyl adipate, dimethicone 100,dimethicone 350, dimethiconol/trimethylsiloxysilicate crosspolymer(40/60 why; 1000000 pa·s), dimethoxane, dimethyl isosorbide, dimethylsulfoxide, dimethylaminoethyl methacrylate-butyl methacrylate-methylmethacrylate copolymer, dinoseb-ammonium, dipropylene glycol, disodiumcocoamphodiacetate, disodium laureth sulfosuccinate, disodium laurylsulfosuccinate, dmdm hydantoin, docusate sodium, duro-tak 280-2516,duro-tak 87-2070, duro-tak 87-2194, duro-tak 87-2979, edetate calciumdisodium, edetate disodium, edetate disodium anhydrous, edetate sodium,edetate trisodium, edetic acid, emulsifying wax, entsufon, entsufonsodium, ethyl acetate; ethyl myristate, ethyl oleate, ethylcellulose,ethylene glycol, ethylene oxide, ethylene-propylene copolymer,ethylene-vinyl acetate copolymers, ethylenediamine, ethylenediaminedihydrochloride, ethylhexyl hydroxystearate, fatty acid esters, fattyacid pentaerythriol ester, fatty acids, FD&C blue no. 1, FD&C blue no.1-aluminum lake, FD&C blue no. 2, FD&.C green no. 3, FD&C red no. 40,FD&C yellow no. 5, FD&.C yellow no. 6, ferric oxide red, formaldehydesolution, fragrance 91-122, fragrance 9128-y, fragrance balsam pine no.5124, fragrance cream no. 73457, fragrance cs-28197, fragrance p ofl-147, fragrance rbd-9819, fragrance soap, fragrance ungerer n15195,gelatin, gluconolactone, glutaral, glycerin, glyceryl 1-stearate,glyceryl isostearate, glyceryl laurate, glyceryl mono anddipalmitostearate, glyceryl monocaprylate, glyceryl monocitrate,glyceryl monostearate, glyceryl oleate, glyceryl oleate/propyleneglycol, glyceryl palmitate, glyceryl ricinoleate, glyceryl stearate se,glyceryl stearate/peg stearate, glyceryl stearate/peg-100 stearate,glycol stearate, guar gum, hamamelis virginiana top water, hexyleneglycol, high density polyethylene, hyaluronate sodium, hydrocarbon gel,plasticized, hydrochloric acid, hydrogen peroxide, hydrogenated castoroil, hydrogenated soybean lecithin, hydroxyethyl cellulose (2000 mpa·sat 1%), hydroxyethyl cellulose (280 mpa·s at 2%), hydroxyethylcellulose, unspecified, hydroxypropyl cellulose (110000 wamw),hydroxypropyl cellulose (1600000 wamw), hypromellose 2208 (100000mpa·s), hypromellose 2208 (4000 mpa·s), hypromellose 2910 (4000 mpa·s),hypromelloses, icodextrin, imidurea, isobutane, isoodylacrylate/acrylamide/vinyl acetate copolymer, kollidon va 64 polymer,isopropyl alcohol, isopropyl isostearate, isopropyl myristate, isopropylpalmitate, isostearic acid, isostearyl alcohol, kaolin, lactic acid,lactic acid, d1-, lactic acid, 1-, lactose, laneth, lanolin, lanolinalcohol-mineral oil, lanolin alcohols, lanolin cholesterols, lanolinoil, lanolin, ethoxylated, lanosterol, lauramine oxide, laureth sulfate,laureth-2, laureth-23, laureth-4, lauric diethanolamide, lauric myristicmonoethanolamide, lauric/myristic diethanololamide, lavender oil,lecithin, lemon oil, levomenthol, levulinic acid, light mineral oil,limonene, (+)-, linear tridecyl benzene sulfonate, liquid petroleum,magnesium aluminum silicate, magnesium nitrate, magnesium silicate,magnesium stearate, magnesium sulfate, mannitol, medical antiform a-femulsion, medium-chain triglycerides, Mentha spicata oil, menthol,metanil yellow, methyl gluceth-10, methyl gluceth-20, methyl glucosesesquistearate, methyl laurate, methyl salicylate, methyl stearate,methylcellulose, methylchloroisothiazolinone,methylchloroisothiazolinone/methylisothiazolinone mixture, methylparaben, microcrystalline wax, mineral oil, mono and diglyceride,multisterol extract, myristyl alcohol, myristyl lactate, niacinamide,nitric acid, nonoxynol-40, nonoxynol-9, o-tolyl biguanide, octisalate,octoxynol-9, octyldodecanol, oleic acid, oleth-10/oleth-5, oleth-2,oleth-20, oleyl alcohol, oleyl oleate, olive oil, palm oil, paraffin,parfum creme 45/3, peanut oil, peg 6-32 stearate/glycol stearate,peg-100 stearate, peg-120 glyceryl stearate, peg-120 methyl glucosedioleate, peg-2 stearate, peg-20 methyl glucose sesquistearate, peg-20sorbitan isostearate, peg-25 propylene glycol stearate, peg-5 oleate,peg-6 isostearate, peg-60 hydrogenated castor oil, peg-7 methyl ether,peg-75 lanolin, peg-8 laurate, peg-8 stearate, peg/ppg-18/18dimethicone, pegoxol 7 stearate, pentadecalactone, pentasodiutnpentetate, peppermint oil, perfume gd 5604, petrolatum, phenonip,phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phosphoricacid, pigmented polyethylene/polyester 1501 film, pine needle oil (Pinussylvestris), piastibase-50w, poloxamer 124, poloxamer 182, poloxamer188, poloxamer 407, polyacrylic acid (250000 mw), polybutene (1400 mw),polycarbophil, polyester, polyester polyamine copolymer, polyethyleneglycol 1000, polyethylene glycol 1450, polyethylene glycol 1600,polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol3350, polyethylene glycol 400, polyethylene glycol 4000, polyethyleneglycol 540, polyethylene glycol 600, polyethylene glycol 6000,polyethylene glycol 8000, polyethylene glycol 900, polyglyceryl-3oleate, polyisobutylene, polyisobutylene/polybutene adhesive,polyoxyethylene alcohols, polyoxyethylene fatty acid esters, polyoxyl 20cetostearyl ether, polyoxyl 35 castor oil, polyoxyl 40 hydrogenatedcastor oil, polyoxyl 40 stearate, polyoxyl 6 and polyoxyl 32palmitostearate, polyoxyl distearate, polyoxyl glyceryl stearate,polyoxyl stearate, polypropylene, polypropylene glycol,polyquaternium-10, polysorbate 20, polysorbate 40, polysorbate 60,polysorbate 80, polyvinyl alcohol, ponceau 3r, potassium carbonate,potassium chloride, potassium citrate, potassium hydroxide, potassiumsoap, potassium sorbate, povidone k30, povidone k90, povidone/eicosenecopolymer, povidones, powdered cellulose, ppg-12/smdi copolymer, ppg-15stearyl ether, ppg-20 methyl glucose ether distearate, ppg-26 oleate,promulgen d, promulgen g, propane, propionic acid, propyl alcohol,propyl gallate, propylene carbonate, propylene glycol, propylene glycoldiacetate, propylene glycol dicaprylate, propylene glycol monolaurate,propylene glycol monopalmitostearate, propylene glycol monostearate,propylparaben, protein hydrolysate, quaternium-15, quaternium-15cis-form, rhodamine 1), saccharin, saccharin sodium, scotchpak 1022, sdalcohol 40, sd alcohol 40-2, sd alcohol 40b, sepineo p 600, silicon,silicon dioxide, silicone, silicone adhesive 4302, silicone emulsion,silicone/polyester film strip, simethicone, simethicone emulsion, soap,sodium acetate, sodium acetate anhydrous, sodium alginate, sodiumbenzoate, sodium bisulfite, sodium borate, sodium carbonate, sodiumcetostearyl sulfate, sodium chloride, sodium cocoyl isethionate, sodiumformaldehyde sulfoxylate, sodium hydroxide, sodium iodide, sodiumlactate, sodium laureth-2 sulfate, sodium laureth-3 sulfate, sodiumlaureth-5 sulfate, sodium lauroyl sarcosinate, sodium lauryl sulfate,sodium lauryl sulfoacetate, sodium metabisulfite, sodium metaphosphate,insoluble, sodium methyl cocoyl taurate, sodium phosphate, sodiumphosphate, dibasic, sodium phosphate, dibasic, anhydrous, sodiumphosphate, dibasic, dihydrate, sodium phosphate, dibasic, heptahydrate,sodium phosphate, monobasic, sodium phosphate, monobasic, anhydrous,sodium phosphate, monobasic, dihydrate, sodium phosphate, monobasic,monohydrate, sodium polyacrylate, sodium pyrrolidone carboxylase, sodiumsilicate, sodium sulfate, sodium sulfate anhydrous, sodium sulfite,sodium tallowate, beef, sodium thiosulfate, sorbic acid, sorbitanmonolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan sesquioleate, sorbitan tri stearate, sorbitol,soybean, soybean oil, spermaceti, squalane, stannic chloride, stannouschloride anhydrous, starch, stearalkonium chloride, stearamidoethyldiethylamine, steareth-10, steareth-100, steareth-2, steareth-21,steareth-40, stearic acid, stearic diethanolamide, stearic hydrazide,stearoyl polyoxylglycerides, stearyl alcohol, styrene/isoprene/styreneblock copolymer, succinic acid, sucrose, sucrose stearate, sulfuricacid, talc, tallow glycerides, tartaric acid, tegacid, tenox, tenox-2,tert-butyl alcohol, thimerosal, thyme oil, titanium dioxide, tocopherol,tragacanth, triacetin, trichloromonofluoromethane, trideceth-10,triethanol amine lauryl sulfate, trihydroxystearin, trimethylsilyltreated dimethiconolltrimethylsiloxysilicate crosspolymer (40/60% w/w;5000000 pa·s), trimethylsilyl treateddimethiconolltrimethylsiloxysilicate crosspolymer (45/55% w/w; 100000pa.$), trisodium citrate dihydrate, trisodium hedta, trolamine,tromethamine, tyloxapol, undecylenic acid, urea; vanillin, vegetableoil, vegetable oil, hydrogenated, wax, wecobee fs, white wax, xanthangum, yellow wax, zinc acetate, zinc oxide, and zinc stearate.

Antioxidants

In some embodiments, the compositions of the disclosure containantioxidants. Antioxidants are substances that inhibit oxidation.Non-limiting examples of antioxidants that can be used with thecompositions of the present invention include acetyl cysteine, ascorbicacid polypeptide, ascorbyl dipalmitate, ascorbyl methylsilanolpectinate, ascorbyl palmitate, ascorbyl stearate, butated hydroxyanisole(BHA), butylated hydroxytoluene (BHT), t-butyl hydroquinone, cysteine,cysteine HCl, diamylhydroquinone, di-t-butylhydroquinone, dicetylthiodipropionate, dioleyl tocopheryl methylsilanol, disodium ascorbylsulfate, distearyl thiodipropionate, ditridecyl thiodipropionate,dodecyl gallate, erythorbic acid, esters of ascorbic acid, ethylferulate, ferulic acid, gallic acid esters, hydroquinone, isooctylthioglycolate, kojic acid, magnesium ascorbate, magnesium ascorbylphosphate, methylsilanol ascorbate, natural botanical anti-oxidants suchas green tea or grape seed extracts, nordihydroguaiaretic acid, octylgal late, phenylthioglycolic acid, potassium ascorbyl tocopherylphosphate, potassium sulfite, propyl gallate, quinones, rosmarinic acid,sodium ascorbate, sodium bisulfite, sodium erythorbate, sodiummetabisulfite, sodium sulfite, superoxide dismutase, sodiumthioglycolate, sorbityl furfural, thiodiglycol, thiodiglycolamide,thiodiglycolic acid, thioglycolic acid, thiolactic acid, thiosalicylicacid, tocophereth-5, tocophereth-10, tocophereth-12, tocophereth-18,tocophereth-50, tocopherol, tocophersolan, tocopheryl acetate,tocopheryl linoleate, tocopheryl nicotinate, tocopheryl succinate, andtris(nonylphenyl)phosphite.

Other Ingredients

In some embodiments, sorbitol is added to the rofecoxib topicalcompositions described herein. In some embodiments, sorbitol is ahydrator. In some embodiments, sorbitol is a moisturizer. In someembodiments, sorbitol is a humectant. In some embodiments, polyvinylalcohol is added to the rofecoxib topical compositions described herein.In some embodiments, polyvinyl alcohol is used to increase the viscosityof the rofecoxib topical composition. In some embodiments,2-hydroxyethyl stearate is added to the rofecoxib topical compositions.In some embodiments, 2-hydroxyethyl stearate is used to give therofecoxib topical composition a waxy feel. In some embodiments, cetylalcohol is added to the rofecoxib topical compositions described herein.In some embodiments, cetyl alcohol is a thickener. In some embodiments,cetyl alcohol is an emulsifier. In some embodiments, glycerolmonosterate is added to the rofecoxib topical compositions describedherein. In some embodiments, glycerol monosterate is a thickener. Insome embodiments, glycerol monostearate is an emulsifier. In someembodiments, beeswax is used in the rofecoxib topical compositionsdescribed herein. In some embodiments, beeswax is used as a thickener.In some embodiments, urea is added to rofecoxib topical compositions. Insome embodiments, urea is added as an emollient or a penetration agent.

In some embodiments, OA is added to the topical composition as apenetration enhancer, or a reagent which facilitates entry of rofecoxibinto the skin. In some embodiments, PGD is added to the topicalcomposition as a penetration enhancer. In some embodiments, DGME isadded to the topical composition as a penetration enhancer. In someembodiments, sodium dodecyl sulfate (SDS) is added to the compositions.In some embodiments, SDS serves as a penetration enhancer. In someembodiments, menthol is added to the rofecoxib topical compositions. Insome embodiments, menthol is a penetration enhancer or enhances thesmell of the rofecoxib topical compositions. In some embodiments,beeswax is added to the rofecoxib topical compositions. In someembodiments, beeswax is a thickener. In some embodiments, beeswax is apenetration enhancer. In some embodiments, polyethylene glycol is addedto the compositions. Polyethylene glycol is an oligomer or polymer ofethylene oxide. In some embodiments, the PEG is selected frompolyethylene glycol 400, polyethylene glycol 350, polyethylene glycol3350, polyethylene glycol 4000, polyethylene glycol 1500, polyethyleneglycol 6000, and polyethylene glycol 8000.

In some embodiments, the rofecoxib topical composition comprisesspearmint oi some embodiments, the spearmint oil is an extract of Menthaspicata.

In some embodiments, the rofecoxib topical composition comprises AC, BA,and Rofecoxib. In some embodiments, the rofecoxib topical compositioncomprises DI, PC, and Rofecoxib. In some embodiments, the rofecoxibtopical composition comprises DI, PC, BA, and Rofecoxib. In someembodiments, the rofecoxib topical composition comprises DI, PC, DMSO,BA, and Rofecoxib. In some embodiments, the rofecoxib topicalcomposition comprises DI, PC. DMSO, and Rofecoxib. In some embodiments,the rofecoxib topical composition comprises DI, PC, BA, OA, andRofecoxib. In some embodiments, the rofecoxib topical compositioncomprises IN, PC, BA, DMSO, AT, and Rofecoxib. In some embodiments, therofecoxib topical composition comprises DI, PC, BA, DGME, DMSO, andRofecoxib. In some embodiments, the rofecoxib topical compositioncomprises DI, PC, BA, DMSO, OA, and Rofecoxib. In some embodiments, therofecoxib topical composition comprises DI, PC, BA, DMSO, PS-20, andRofecoxib. In some embodiments, the rofecoxib topical compositioncomprises DI, PC, BA, DMSO, PS20, and Rofecoxib. In some embodiments,the rofecoxib topical composition comprises DI, PC, BA, DMSO, PS60, and.Rofecoxib. In some embodiments, the rofecoxib topical compositioncomprises DI, PC, BA, OA, DMSO, and Rofecoxib. In some embodiments, therofecoxib topical composition comprises DI, DMSO, PC, BA, Lanolin, PPG,and Rofecoxib. In some embodiments, the rofecoxib topical compositioncomprises DI, DMSO, PC, BA, Lanolin, PEG-400, and Rofecoxib. In someembodiments, the rofecoxib topical composition comprises DI, DMSO, PC,BA, Lanolin, MineralOil, and Rofecoxib. In some embodiments, therofecoxib topical composition comprises DI, DMSO, PC, BA, Petroleum,MineralOil, and Rofecoxib. In some embodiments, the rofecoxib topicalcomposition comprises DI, PC, BA, AT, OA, DMSO, and Rofecoxib. In someembodiments, the rofecoxib topical composition comprises DI, PC, BA,DEME, DMSO, OA, and Rofecoxib. In some embodiments, the rofecoxibtopical composition comprises DI, PC, BA, DGMF, DMSO, AT, and Rofecoxib.In some embodiments, the rofecoxib topical composition comprises DI, PC,BA, OA, PS20, DMSO, and Rofecoxib. In some embodiments, the rofecoxibtopical composition comprises DI, PC, BA, DMSO, PS80, OA, and Rofecoxib.In some embodiments, the rofecoxib topical composition comprises DI, PC,BA, DMSO, PS60, OA, and Rofecoxib. In some embodiments, the rofecoxibtopical composition comprises DI, PC, BA, OA, DMSO, PEG, and Rofecoxib.In some embodiments, the rofecoxib topical composition comprises DI, PC,BA, DMSO, OA, PEG, and Rofecoxib. In some embodiments, the rofecoxibtopical composition comprises DI, DMSO, PC, BA, Lanolin, Mineral Oil,PBS/Xanthan Gum, and Rofecoxib. In some embodiments, the rofecoxibtopical composition comprises DI, PC, BA, AT, OA, PS20, DMSO, andRofecoxib. In some embodiments, the rofecoxib topical compositioncomprises DI, PC, BA, DGME, OA, PS20, DMSO, and Rofecoxib. In someembodiments, the rofecoxib topical composition comprises DI, PC, BA, OA,DMSO, Glycerol monostearate, Mineral Oil, and Rofecoxib. In someembodiments, the rofecoxib topical composition comprises DI, PC, BA, OA,DMSO, Lanoline, and Rofecoxib. In some embodiments, the rofecoxibtopical composition comprises DI, PC, BA, OA, DMSO, Lanoline, OliveOil,and Rofecoxib. In some embodiments, the rofecoxib topical compositioncomprises DI, PC, BA, OA, DMSO, Lanoline, OliveOil, and Rofecoxib. Insome embodiments, the rofecoxib topical composition comprises DI, PC,DMSO, BA, OleicAcid, Lanolin, Mineral Oil, and Rofecoxib. In someembodiments, the rofecoxib topical composition comprises DI, PC, BA,DMSO, OA, PEG, Lanoline, and Rofecoxib. In some embodiments, therofecoxib topical composition comprises DI, PC, BA, DMSO, OA, PEG, IPTD,and Rofecoxib. In some embodiments, the rofecoxib topical compositioncomprises DI, PC, BA, DMSO, OA, PEG, PGD, and Rofecoxib. In someembodiments, the rofecoxib topical composition comprises DI, PC, DMSO,OA, PEG, PS80, and Rofecoxib. In some embodiments, the rofecoxib topicalcomposition comprises DI, PC, BA, DMSO, OA, PEG, PPG, and Rofecoxib. Insome embodiments, the rofecoxib topical composition comprises DI, PC,BA, DMSO, OA, PEG, PS20, and Rofecoxib. In some embodiments, therofecoxib topical composition comprises DI, PC, BA, DMSO, OA, PEG. EA,and Rofecoxib. Iii some embodiments, the rofecoxib topical compositioncomprises DI, PC, BA, DMSO, OA, PEG, DGME, and Rofecoxib. In someembodiments, the rofecoxib topical composition comprises DI, PC, BA,DMSO, OA, PEG, Alpha-Terpinol, and Rofecoxib. In some embodiments, therofecoxib topical composition comprises DI, BA, DMSO, OA, PEG, DIA, andRofecoxib. In some embodiments, the rofecoxib topical compositioncomprises DI, PC, BA, DMSO, OA, PEG, DS, and Rofecoxib. In someembodiments, the rofecoxib topical composition comprises DI, PC, BA,DMSO, OA, PEG, M24D, and Rofecoxib. In some embodiments, the rofecoxibtopical composition comprises DI, PC, BA, DMSO, OA, PEG, Mineral Oil,and Rofecoxib. In some embodiments, the rofecoxib topical compositioncomprises DI, PC, BA, DMSO, OA, DIA, PEG, and Rofecoxib. In someembodiments, the rofecoxib topical composition comprises DI, PC, BA,DMSO, OA, DIA, PEG, and Rofecoxib. In some embodiments, the rofecoxibtopical composition comprises DI, PC, BA, DMSO, EA, DIA, OA, andRofecoxib. In some embodiments, the rofecoxib topical compositioncomprises DI, PC, BA, DMSO, DIA, PS20, DGME, and Rofecoxib. In someembodiments, the rofecoxib topical composition comprises DI, PC, BA,DMSO, DIA, PS20, PG, and Rofecoxib. In some embodiments, the rofecoxibtopical composition comprises DI, PC, BA, DGME, DMSO, AT, OA, DGME, andRofecoxib. In some embodiments, the rofecoxib topical compositioncomprises DI, PC, BA, DOME, AT, OA, PS20, DMSO, and Rofecoxib. In someembodiments, the rofecoxib topical composition comprises DI, PC, BA, OA,DMSO, Beeswax, Lanoline, MineralOil, and. Rofecoxib. In someembodiments, the rofecoxib topical composition comprises DI, DMSO, BA,OA, Lanolin, Mineral Oil, BeesWax, and Rofecoxib. In some embodiments,the rofecoxib topical composition comprises DI, PC, BA, DMSO, OA,Lanolin, Mineral Oil, BeesWax, and Rofecoxib. In some embodiments, therofecoxib topical composition comprises Rofecoxib, DI, PC, BA, DMSO, OA,Lanolin, MineralOil, and BeesWax. In some embodiments, the rofecoxibtopical composition comprises Rofecoxib, DI, PC, BA, DMSO, OA, Lanolin,and BeesWax. In some embodiments, the rofecoxib topical compositioncomprises DI, PC, BA, DMSO, OA, PEG, IPTD, SDS, and Rofecoxib. In someembodiments, the rofecoxib topical composition comprises DI, BA, DMSO,OA, PEG, PGD, Lanoline, and Rofecoxib. In some embodiments, therofecoxib topical composition comprises DI, PC, BA, DMSO, OA, PEG,BeesWax, PS80, and Rofecoxib. In some embodiments, the rofecoxib topicalcomposition comprises DI, PC, BA, DMSO, OA, DIA, PEG, Rofecoxib, and. Insome embodiments, the rofecoxib topical composition comprises DI, PC,BA, DMSO, EA, DIA, AT, OA, and Rofecoxib. In some embodiments, therofecoxib topical composition comprises DI, PC, BA, DMSO, PS20, DGME,OA, and Rofecoxib. In some embodiments, the rofecoxib topicalcomposition comprises DI, PC, BA, DMSO, DIA, PS20, AT, DGMF, andRofecoxib. In some embodiments, the rofecoxib topical compositioncomprises DI, PC, BA, DMSO, DIA, PS20, OA, PPG, and Rofecoxib. In someembodiments, the rofecoxib topical composition comprises DI, PC, BA,DMSO, DIA, PS20, PGD, DOME, and Rofecoxib. In some embodiments, therofecoxib topical composition comprises DI, PC, BA, DMSO, DIA, PS20,PGD, AT, and Rofecoxib. In some embodiments, the rofecoxib topicalcomposition comprises DI, PC, BA, DMSO, DIA, PS20, PGD. AT, andRofecoxib. In some embodiments, the rofecoxib topical compositioncomprises DI, PC, BA, DMSO, DIA, PS20, AT, DGME, and Rofecoxib. In someembodiments, the rofecoxib topical composition comprises IN, PC, BA,DMSO, EA, DIA, Rofecoxib, PS20, and Menthol. In some embodiments, therofecoxib topical composition comprises DI, PC, BA, DMSO, DIA, PS20,PGD, OA, DOME, and Rofecoxib. In some embodiments, the rofecoxib topicalcomposition comprises DI, PC, BA, DMSO, DIA, PS20, AT, OA, DGME, andRofecoxib. In some embodiments, the rofecoxib topical compositioncomprises DI, PC, BA, DMSO, DIA, PS20, PGD, AT, DOME, and Rofecoxib. Insome embodiments, the rofecoxib topical composition comprises DI, PC,BA, DMSO, DIA, PS20, PGD, AT, DOME, and Rofecoxib. In some embodiments,the rofecoxib topical composition comprises DI, PC, BA, DMSO, EA,Rofecoxib, DIA, AT, BeesWax, Menthol, and Eucalyptus. In someembodiments, the rofecoxib topical composition comprises DI, PC, BA,DMSO, DIA, PS20, PGD, OA, DGME, Rofecoxib, and Lanoline.

In some embodiments, the rofecoxib topical composition is selected fromTable 5. In some embodiments, the rofecoxib topical composition isselected from Formulations 1-77, 80, 82, 83, and 85493.

In some embodiments, the rofecoxib topical composition is Formulation82. Formulation 82 comprises DI (15% w/w), PC (5% w/w), BA (2.5% w/w)DMSO (20% w/w), DIA (12% w/w), PS20 (15% w/w), DGME (18.5% w/w), OA (5%w/w), Rofecoxib (2% w/w), Spearmint (0.33% w/w), and Eucalyptus oil(0.67% w/w).

In some embodiments, the rofecoxib topical composition is Formulation85. Formulation 85 comprises DI (15% w/w), PC (5% w/w), BA (2.5% w/w),DMSO (20% w/w), DIA (12% w/w), DGME (18.5% w/w), PS20 (15% w/w), OA (5%w/w), Hydoxypropyl cellulose 100,000 (4% w/w), Rofecoxib 2% (2% w/w),Eucalyptus Oil (0.33% w/w), and Spearmint Oil (0.67% w/w).

Properties and Stability of Rofecoxib Topical Compositions

In some embodiments, the compositions of the disclosure are stable forabout 6 or more months. In some embodiments, the compositions of thedisclosure are stable for about 6 months, about 7 months, about 8months, about 9 months, about 10 months, about 11 months, about 12months, about 13 months, about 14 months, about 15 months, about 16months, about 17 months, about 18 months, about 19 months, about 20months, about 21 months, about 2.2 months, about 23 months, about 24months, about 25 months, about 26 months, 27 months, about 28 months,about 29 months, about 30 months, about 31 months, about 32 months,about 33 months, about 34 months, about 35 months, about 36 months,about 37 months, about 38 months, about 39 months, about 40 months,about 41 months, about 42 months, about 43 months, about 44 months,about 45 months, about 46 months, about 47 months, about 48 months,about 5 years, about 6 years, about 7 years, about 8 years, about 9years, about 10 years, or more, including all values and ranges inbetween. In some embodiments, the compositions of the disclosure arestable for at least 6 months. In some embodiments, the compositions ofthe disclosure are stable for at least 24 months.

In some embodiments, a stable composition of the disclosure is yellow.In some embodiments, a stable composition of the disclosure is lightyellow.

In some embodiments, the compositions of the disclosure are stable fromabout pH 3.5 to about pH 8.5. In some embodiments, the rofecoxib topicalcompositions are stable at about pH 3.5, about pH 4.0, about pH 4.5,about pH 5.0, about pH 5.5, about pH 6.0, about pH 6.5, about pH 7.0,about pH 7.5, about pH 8.0, or about pH 8.5, including all values andranges in between.

In some embodiments, the compositions of the disclosure are stable at atemperature range from about 0° C. to about 50° C. In some embodiments,the compositions of the disclosure are stable at about 25° C. In someembodiments, the compositions of the disclosure are stable at about 30°C. In some embodiments, the compositions of the disclosure are stable atabout 35° C. In some embodiments, the compositions of the disclosure arestable at about 40° C. In some embodiments, the compositions of thedisclosure are stable at about 45° C. In some embodiments, thecompositions of the disclosure are stable at about 50° C.

In some embodiments, a stable rofecoxib topical composition refers to acomposition in which rofecoxib does not appreciably precipitate. In someembodiments, a stable rofecoxib topical composition refers to acomposition in which >95% of rofecoxib does not precipitate. In someembodiments, a stable rofecoxib topical composition refers to acomposition in which >90% of rofecoxib does not precipitate.Alternatively stated, a stable rofecoxib topical composition refers to acomposition with less than about 5%, less that about 4%, less than about3%, less than about 2%, less than about 1%, less than about 0.5%, orless than about 0.1% undissolved rofecoxib (relative to the total amountof rofecoxib in the composition). In other embodiments, a stableformulation refers to a formulation which does not separate intoseparate phases.

in some embodiments, the rofecoxib topical compositions provided hereinare sufficiently bodied such that the product does not fall off thetargeted dosing area. In some embodiments, the rofecoxib topicalcompositions provided herein do not run-off the application site untilthe topical composition is rubbed in to the skin. In some embodiments,the rofecoxib topical compositions provided herein penetrate the skin.

In some embodiments, the flux of the rofecoxib topical compositionsdescribed herein is superior to other NSAIDS, including ibuprofen,diclofenac, celecoxib, diflunisal, indomethacin, aspirin, naproxen,oxaprozin, piroxicam, salsalate, sulindac, and tolmetin. In someembodiments, the flux of the rofecoxib topical compositions describedherein is superior to diclofenac. In some embodiments, application ofthe rofecoxib topical compositions described herein to the skin treatpain more effectively than diclofenac. In some embodiments, applicationof the rofecoxib topical compositions described herein to the skin treatinflammation more effectively than diclofenac. In some embodiments,application of the rofecoxib topical composition results in a higherpenetration amount into the blood than diclofenac, 0.067 mg ofdiclofenac penetrates into the blood after 24 hours after 25 hours.

In some embodiments, the rofecoxib topical compositions described hereinare non-irritating. In some embodiments, the rofecoxib topicalcompositions described herein are suitable for chronic use.

Products Containing Rofecoxib Topical Compositions

In some embodiments, the rofecoxib topical compositions of thedisclosure are mixed with a vehicle to form a product. Methods ofpreparing products for topical administration are known in the art (see,for example, Remington's Pharmaceutical Sciences, 2000-20th edition, andThe United States Pharmacopeia: The National Formulary, USP 24 NF19,published in 1999, which is incorporated by reference in its entiretyherein).

In some embodiments, the vehicle is utilized to facilitate delivery ofthe rofecoxib topical composition to the skin. Non-limiting examples ofvehicles include liposomes, nanosomes, emulsions, microemulsions,nanocapsules, solid lipid nanoparticles, hydrogels, and nanocrystals.The vehicle may contain any ingredient listed throughout thisdisclosure.

In some embodiments, the vehicle is a liposome. Liposomes are vesicularstructures, which have an aqueous core enclosed by a lipid bilayer. Insome embodiments, liposomes contain phospholipids or fatty acids. Insome embodiments, liposomes range in size from 15 nm in diameter toseveral micrometers in diameter. In some embodiments, liposomes exhibita unilamellar structure or a multilamellar structure. Liposomesfacilitate the continuous supply of active ingredients or additionalingredients to cells over a sustained period of time.

In some embodiments, the vehicle is an emulsion. An emulsion is adispersed system containing at least two immiscible liquid phases, oneof which is dispersed in the form of small droplets throughout theother, and an emulsifying agent to improve the stability of the system.Non-limiting examples of emulsions include water-in-oil emulsions,oil-in-water emulsions, and oil-in-oil emulsions. Non-limiting examplesof emulsifying agents include esters of glycerin, esters of propyleneglycol, fatty acid esters of polyethylene glycol, fatty acid esters ofpolypropylene glycol, esters of sorbitol, esters of sorbitan anhydrides,carboxylic acid copolymers, esters and ethers of glucose, ethoxylatedethers, ethoxylated alcohols, alkyl phosphates, polyoxyethylene fattyether phosphates, fatty acid amides, acyl lactylates, soaps, TEAstearate, DEA oleth-3 phosphate, polyethylene glycol 20 sorbitanmonolaurate (polysorbate 20), polyethylene glycol 5 soya sterol,steareth-2, steareth-20, steareth-21, ceteareth-20, cetearyl glucoside,cetearyl alcohol. C12-13 pareth-3, PPG-2 methyl glucose etherdistearate, PPG-5-ceteth-20, his-PEG/PPG-20/20 dimethicone, ceteth-10,poly sorbate 80, polysorbate 21, poly sorbate 61, polysorbate 81,polysorbate 85, cetyl phosphate, potassium cetyl phosphate,diethanolamine cetyl phosphate, polysorbate 60, glyceryl stearate,PEG-100 stearate, arachidyl alcohol, arachidyl glucoside, and mixturesthereof.

In some embodiments, “oil” signifies the oil phase of an emulsion.Non-limiting examples of oils which may be utilized within the oil phaseinclude hydrocarbon oils of animal origin and hydrocarbon oils ofvegetable origin. Non-limiting examples of hydrocarbon oils of vegetableorigin include liquid triglycerides of fatty acids comprising 4 to 10carbon atoms such as triglycerides of heptanoic or octanoic acids oralso, for example, sunflower, corn, and soy, pumpkin, grape seeds,sesame, hazelnut, apricot, macadamia, arara, sunflower, castor, avocado,and triglycerides of caprylic/capric acids. In some embodiments, the oilphase of the emulsion contains from about 10 why to about 90% w/w. Insome embodiments, the oil phase of the emulsion is about 5% w/w, orabout 10% w/w; or about 15% w/w, or about 20% w/w, or about 25% w/w, orabout 30% w/w, or about 35% w/w, or about 40% w/w, or about 45% w/w, orabout 50% w/w, or about 55% w/w, or about 60% w/w, or about 65% w/w, orabout 70% w/w, or about 75% w/w, or about 80% w/w, or about 85% w/w, orabout 90% w/w.

In some embodiments, “water” signifies the water phase of an emulsion.In some embodiments, the water phase of the emulsion contains from about10% w/w to about 90% w/w. In some embodiments, the water phase of theemulsion is about 5% w/w, or about 10% w/w, or about 15% w/w, or about20% w/w; or about 25% w/w, or about 30% w/w, or about 35% w/w, or about40% w/w, or about 45% w/w, or about 50% w/w, or about 55% w/w, or about60% w/w, or about 65% w/w, or about 70% w/w, or about 75% w/w, or about80% w/w, or about 85% w/w, or about 90% w/w.

In some embodiments, the rofecoxib topical compositions of thedisclosure are incorporated into a lotion, ointment, cream, gel,suspension, powder, or any other type of liquid or solid compositionsused for topical application.

Methods of Using Rofecoxib Topical Compositions

In some embodiments, the rofecoxib topical compositions of thedisclosure are used for treating inflammation and/or pain.

In some embodiments, the rofecoxib topical compositions of thedisclosure are administered topically to the skin.

In some embodiments, the rofecoxib topical compositions described hereinare applied topically to a subject's skin. In some embodiments, thesubject is a mammal. In some embodiments, the subject is an animal or ahuman. Non-limiting examples of animals include dogs, cats, wolves,bears, tigers, lions, monkeys, guinea pigs, ferrets, pigs, hamsters, andrabbits.

In some embodiments, the rofecoxib topical compositions are applied tothe skin. In some embodiments, the compositions of the disclosure areapplied to the epidermis. In some embodiments, the compositions of thedisclosure penetrate the dermis. In some embodiments, the compositionsof the disclosure penetrate the hypodermis. In some embodiments, thecompositions of the disclosure are applied to the face, scalp, hands,neck, décolleté, scalp, paw, hand, palm, arm, leg, foot, sole, chest,breast, back, abdomen, buttock, vulva, eyelid, nipples, penis, scrotum,anus, or any other skin areas of a subject. In some embodiments, thecompositions of the disclosure are applied to the lips. In someembodiments, the composition is applied to the whole body.

In some embodiments, the rofecoxib topical compositions are applied as alotion, ointment, cream, gel, suspension, powder, or any other type ofliquid or solid compositions used for topical application.

In some embodiments, the rofecoxib topical compositions are left on theskin for a period of at least 1 minute, or at least 2 minutes, or atleast 3 minutes, or at least 4 minutes, or at least 5 minutes, or atleast 6 minutes, or at least 7 minutes, or at least 8 minutes, or atleast 9 minutes, or at least 10 minutes, or at least 15 minutes, or atleast 20 minutes, or at least 25 minutes, or at least 30 minutes, or atleast 45 minutes, or at least 1 hour, or at least 12 hours, or up to 24hours, including all ranges in between.

In some embodiments, the rofecoxib topical compositions are applied oneor more times per day. In some embodiments, the compositions are appliedonce per day. In some embodiments, the compositions are applied twiceper day. In some embodiments, the compositions are applied twice a day,or three times a day, or four time a day, or more. In some embodiments,the compositions are applied every day, or every other day, or everythird day, or every fourth day, or every fifth day, or every sixth day,or once per week.

In some embodiments, the rofecoxib topical compositions are suitable forlong-term use. In some embodiments, rofecoxib topical compositions areutilized at least once a week for two weeks or more. In someembodiments, rofecoxib topical compositions are utilized for at leastabout 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks,about 11 weeks, about 12 weeks, about 3 months, about 4 months, about 5months, about 6 months, about 7 months, about 8 months, about 9 months,about 10 months, about 11 months, about 12 months, about 2 years, about3 years or more.

In some embodiments, the rofecoxib topical compositions are applied whena subject experiences pain. In some embodiments, the rofecoxib topicalcompositions are applied when a subject experiences inflammation. Insome embodiments, the rofecoxib topical compositions are appliedprophylactically, e.g. to prevent future pain or inflammation.

In some embodiments, application of a rofecoxib topical compositionresults in pain relief. In some embodiments, application of a rofecoxibtopical composition results in relief from chronic pain. In someembodiments, application of a rofecoxib topical composition results inrelief from acute pain.

In some embodiments, the rofecoxib topical compositions are used totreat one or more diseases selected from the group consisting ofarthritis, osteoarthritis, juvenile rheumatoid arthritis, joint pain dueto injury e.g. ankle sprains, sports injuries, carpal tunnel syndrome,ankle sprains, rheumatoid arthritis, inflammation, low back pain,ankylosing spondylitis, psoriatic arthritis, tennis elbow, headache, andmigraine.

EXAMPLES Example 1. Determination of Solubility of Rofecoxib in VariousSolvent Systems

The solubility of rofecoxib was tested in a variety of solvent systemsby UV spectrophotometry. A UV spectrophotometry method of evaluating thesolubility of rofecoxib was used to determine the solubility ofrofecoxib in various solvent systems. Erk et al. describes this methodand is incorporated by reference herein in its entirety: Erk et al.Pharmazie. 2004 June; 59(6):453-6.

General Methods: Calculating the Extinction coefficient of rofecoxib:100 mg of rofecoxib was dissolved in 100 ml of methanol. Dilutions ofthe stock solution were made into methanol to give a final rofecoxibconcentration of 5 μg/ml, 10 μg/ml, 20 μg/ml, 25 μg/ml, 30 μg/ml, 35μg/ml, 40 μg/ml, 45 μg/ml, and 50 μg/ml. A UV spectrophotometer wasutilized to read the absorbance of the samples 279.1 nm. Using Beer'slaw, a value for the extinction coefficient for rofecoxib was obtained.The value of the extinction coefficient of rofecoxib was determined tobe 29.06 and was utilized in future experiments to determine theconcentration of rofecoxib in various solvent systems. FIG. 1 shows theexperimental data for calculation of the extinction coefficient.

Solvent Systems Comprising Single Solvents: 100 mg of rofecoxib wasadded to 1 gram of each solvent. If the solubility of rofecoxib in thesolvent was higher than 100 mg/g, an additional 100 mg of rofecoxib wasadded to the solution. The mixtures of rofecoxib and solvents werevortexed for one minute and left at room temperature for one hour. Themixture was vortexed a second time and then left at room temperatureovernight. The next morning the samples were vortexed a third time andthen centrifuged at 12 k for 5 minutes. The excipient/rofecoxib mixturewas transferred to a new tube being careful to not take any of thepellet. Serial dilutions of the rofecoxib solvent solutions were made(1:100 v:v), (1:1000 v/v), and (1:2000 v/v). Solvents without rofecoxibwere diluted with methanol and used to blank a Beckman DU-7400spectrophotometer. The absorbance of the samples was determined at awavelength of 279.1 nm. The concentration of rofecoxib dissolved in thesolvent was calculated using Beer's Law. Concentrations were convertedfrom units of mg/mL to units of mg/g according to the followingprocedure:

(a) The volume of 1 g of solvent times the calculated mg/ml rofecoxibequals total mg of rofecoxib in 1 g of solvent. e.g. 1 g of a solventthat has a density of 105 g/mL is 952 μL. A rofecoxib solution with aconcentration of rofecoxib of 29.06 mg/mL contains 28.17 mg of rofecoxibin 952 μL of solvent.

(b) To calculate the total volume, a mg of rofecoxib is assumed to equalto 1 μl of volume. Add volume of the solvent to the total weight ofrofecoxib, 28.17 mg 1000 mg of solvent =1028.17 mg.

(c) To calculate the w/w divide the mg of rofecoxib 28.71 mg by thetotal weight of rofecoxib with solvent 1028.71 mg and multiply times1000 mg to get the w/w 2.871 mg/1028.71 mg*1000 mg=28.62 mg/g ofsolvent.

The solubility of rofecoxib in various solvents is shown in Table 2 andFIG. 2.

TABLE 2 Solubility of Rofecoxib in Solvent Systems containing onesolvent Solvent Solubility of rofecoxib (mg/g) N-methyl-2-pyrrolidone198 Dimethyl Sulfoxide 143.6 Propylene Carbonate 49.43 DimethylIsosorbide 39.14 Acetone 23.58 Benzyl Alcohol 19.54 Polyethyleneglycol-400 (PEG) 13.14 Polysorbate 80 (PS80) 9.71 Polysorbate 20 (PS20)9.18 Diethylene glycol monoethyl ether 9.07 Propylene glycol diacetate6.93 Ethyl acetate 5.5 Diisopropyl adipate 2.04 Diethyl sebacate 1.32-Methylpentane-2,4-diol 0.59 Oleic acid 0.402 alpha-Terpineol 95.0+%0.313 Propylene Glycol 0.302 Isopropyl tetradecanoate 0.0017

Solvent Systems Comprising Two or Three Solvents: The solubility ofrofecoxib in solvent systems containing two or three solvents wasdetermined. In solvent systems containing two solvents, 500 μg of eachsolvent was added to 100 mg of rofecoxib. In solvent systems containingthree solvents, 333 μg of each solvent was added to 100 mg of rofecoxib.The samples were mixed using the protocol for solvent systems containingsingle solvents above. Serial dilutions of the rofecoxib solventsolutions were made (1:100 v:v), (1:1000 v/v), and (1:2000 v/v).Solvents without rofecoxib were diluted with methanol and used to blanka Beckman DU-7400 spectrophotometer. The absorbance of the samples wasdetermined at a wavelength of 279.1 nm. The concentration of rofecoxibdissolved in the solvent was calculated using Beer's Law. The ability ofthe solvent systems to synergistically dissolve rofecoxib orantagonistically dissolve rofecoxib (reduce the ability of rofecoxib todissolve was determined) according to the protocol below.

Determination Synergistic or Antagonist Effect of Solvent SystemsContaining Two or Three Solvents: The contribution for solubility of asingle solvent in a two-mixture solution was calculated to be ½ of thecalculated solubility of rofecoxib in one gram of excipient. Likewise,the contribution for solubility of a three-mixture was calculated to be⅓ of the calculated solubility of rofecoxib in one gram of excipient.The expected solubility for a mixture is the addition of thecontribution of each excipient. For example, the solubility of rofecoxibin acetone is 23.58 mg/g, and the solubility of rofecoxib in benzylalcohol is 19.54 mg/g. In a solvent system containing equal amounts ofeach solvent, the expected solubility of rofecoxib in 500 μg of acetoneis 11.79 mg/g and the expected solubility of rofecoxib in 500 μg ofbenzyl alcohol is 9.77 mg/g. The expected solubility of rofecoxib in thesolution containing equal parts benzyl alcohol and acetone is the sum ofthe expected solubilities of rofecoxib in 500 μg of benzyl alcohol andin 500 μg of acetone, or 21.56 mg/g. If the determined solubility ofrofecoxib in a solution containing equal parts acetone and benzylalcohol is greater than 21.56 mg/g rofecoxib, then the solvent systemcontaining equal parts acetone and benzyl alcohol synergisticallydissolves rofecoxib. If the determined solubility of rofecoxib in asolution containing equal parts acetone and benzyl alcohol is less than21.56 mg/g rofecoxib, then the solvent system containing equal partsacetone and benzyl alcohol antagonistically dissolves rofecoxib. Thepercent change between the expected solubility and actual solubility wasdetermined. A solvent system that has a percent change between theexpected solubility and actual solubility of greater than 100% workssynergistically to dissolve rofecoxib. A solvent system that has apercent change between the expected solubility and actual solubility ofless than 100% works antagonistically to dissolve rofecoxib. Similarcalculations are utilized for solvent systems containing three or moresolvents.

Table 3 shows the solubility of rofecoxib in solvent systems containingtwo solvents. Table 4 shows the solubility of rofecoxib in solventsystems containing three solvents.

As shown by Table 3, solvent systems containing BA and AC, AC and PEG,EA and PPG, PEG and EA, AC and DGME, AC and PC, AC and DI, PC and DI,PEG and PGD, AC and PGD, DI and PGD, PC and PGD, EA and DMSO, PEG andPGD, PEG and EA, PEG and DGME, EA and DGME, EA and BA, DGME and PGD, ACand PGD, BA and PGD, and EA and M24D work synergistically to dissolverofecoxib.

As shown by Table 4, the following solvent systems containing threesolvents work synergistically to dissolve rofecoxib: AC, PEG, and PGD;BA, AC, and PEG; BA, PEG, and PGD; PC, AC, and PGD, BA, AC, and PGD; PC,PEG, and PGD; DI, PC, and AC; PC, BA, and AC; DI, PC, and BA; BA, AC,and PEG; PC, AC, and PGD; DI, PC, and EA; BA, AC, and PEG; PC, AC, andPEG; DI, PC, and DGME; DI, PC, and PEG; DI, PC, and PGD; PC, AC, andPGD; DI, BA, and PC; DI, PC, and DMSO; and AC, PEG, and PGD.

TABLE 3 Solubility of Rofecoxib in Solvent Systems containing twosolvents Expected Observed Solvent 1 Solvent 2 Solubility (mg/g)Solubility (mg/g) % Change BA AC 21.54 39.91 185.3 AC PEG 18.34 31.96174.3 EA PPG 2.90 4.53 156.1 BA AC 21.54 32.46 150.7 PEG EA 9.32 14.00150.3 AC DGME 16.30 22.80 139.9 AC PEG 18.34 25.15 137.2 PC AC 36.4849.69 136.2 BA AC 21.54 29.03 134.8 DI AC 31.34 42.18 134.6 DI PC 44.2959.30 133.9 DI PC 44.29 57.83 130.6 PEG PGD 10.04 12.50 124.5 PC AC36.48 45.26 124.1 AC PGD 15.23 18.88 124.0 DI PGD 23.04 28.54 123.9 PCPGD 28.18 34.66 123.0 EA DMSO 74.55 91.63 122.9 PEG PGD 10.04 12.13120.8 EA PEG 9.32 11.19 120.0 PEG DGME 11.11 13.30 119.7 DGME EA 7.298.54 117.3 BA EA 12.52 14.63 116.8 DGME PGD 8.00 9.26 115.7 AC PGD 15.2317.32 113.7 BA PGD 13.24 14.67 110.9 EA M24D 3.05 3.36 110.4 AC EA 14.5215.92 109.7 EA PGD 6.22 6.78 109.1 EA PS20 7.34 7.92 107.9 EA PS80 7.618.05 105.8 DI PEG 26.14 27.65 105.8 EA PC 27.47 28.53 103.9 BA PGD 13.2413.66 103.2 BA AC 31.65 31.86 100.7 EA PGD 6.22 6.23 100.3 PC BA 34.4934.26 99.3 AC MP 110.77 108.48 97.9 PC PGD 28.18 27.55 97.8 DI DGME24.11 22.91 95.0 EA BA 12.52 11.78 94.1 EA DS 3.67 3.22 88.0 EA DIA 3.773.23 85.7 EA AT 2.91 2.40 82.6 EA AC 14.52 11.49 79.1 EA MP 101.75 76.5975.3 DI BA 29.34 21.20 72.3 DI MP 118.57 84.92 71.6 MP EA 107.75 76.8971.4 DI EA 22.32 15.60 69.9 PC MP 123.72 85.76 69.3 BA DGME 14.31 9.1864.2 BA PEG 16.34 10.33 63.2 EA DI 22.32 13.84 62.0 BA PEG 16.34 10.0661.6 BA PEG 16.34 9.91 60.6 EA DGME 7.29 4.04 55.4 AC MP 110.77 58.3852.7 EA IPTD 2.75 1.14 41.5 BA MP 108.77 44.97 41.3 EA OA 2.95 1.14 38.5BA MP 108.77 33.53 30.8 PC AC 36.5 10.3 28.2

TABLE 4 Solubility of Rofecoxib in Solvent Systems containing threesolvents Expected Observed Solubility Solubility Solvent 1 Solvent 2Solvent 3 (mg/g) (mg/g) % Change AC PEG PGD 14.55 55.95 384.56 BA AC PEG18.75 50.86 271.20 BA PEG PGD 13.20 29.64 224.50 PC AC PGD 26.65 53.45200.59 BA AC PGD 16.68 32.89 197.12 DI BA PC 36.04 55.93 155.19 PC PEGPGD 23.17 35.62 153.76 DI PC AC 37.38 53.73 143.72 PC BA AC 30.85 41.57134.75 DI PC BA 36.04 47.68 132.30 BA AC PEG 18.75 24.55 130.90 PC ACPGD 26.65 34.56 129.71 DI PC EA 31.36 40.15 128.04 BA AC PEG 18.75 23.63125.99 PC AC PEG 28.72 35.53 123.74 DI PC DGME 32.55 40.12 123.28 DI PCPEG 33.90 40.38 119.10 DI PC PGD 31.83 36.65 115.12 PC AC PGD 26.6530.43 114.18 DI PC DMSO 77.39 88.47 114.83 AC PEG PGD 14.55 15.15 104.11PC BA DMSO 70.86 60.68 85.64 BA MP PGD 74.82 63.91 85.42 DI BA DMSO67.43 57.35 85.05 PC BA PGD 25.30 21.48 84.91 BA PEG PGD 13.20 11.1984.77 AC MP PGD 76.17 58.79 77.19 PC BA PEG 27.37 17.37 63.48 BA AC MP80.37 38.76 48.23 PC MP PEG 86.86 40.29 46.39 BA MP PEG 76.89 31.0940.43 MP PEG PGD 72.69 25.56 35.17 AC MP PEG 78.24 26.83 34.29 PC AC MP90.34 30.88 34.18 PC MP PGD 84.79 18.40 21.70 PC BA MP 88.99 18.95 21.30

The solubility of rofecoxib compositions containing three or moreingredients was evaluated. The observations are found in Table 5.

TABLE 5 Solubility of Rofecoxib Compositions Containing Three or MoreIngredients Formulation Name Composition Observations Formulation 1 AC(49% w/w), BA (49% Rofecoxib is soluble w/w), Rofecoxib (2% w/w)Formulation 2 DI (49% w/w), PC (49% Rofecoxib is soluble w/w), Rofecoxib(2% w/w) Formulation 3 DI (38.92% w/w), PC Rofecoxib is soluble (12.275%w/w), DMSO (39% w/w), BA (8.0838% w/w), Rofecoxib (2% w/w) Formulation 4DI (15% w/w), DMSO (15% insoluble w/w), PC (5% w/w), BA (2.7% w/w),Lanolin (10% w/w), PPG (50.3% w/w), Rofecoxib (2% w/w) Formulation 5 DI(15% w/w), DMSO (15% insoluble w/w), PC (5% w/w), BA (2.7% w/w), Lanolin(10% w/w), PEG-400 (50.5% w/w), Rofecoxib (2% w/w) Formulation 6 DI (15%w/w), DMSO (15% Seems to separate if it w/w), PC (5% w/w), BA (2.7% isnot stirred. w/w), Lanolin (10% w/w), Mineral Oil (50.5% w/w), Rofecoxib(2% w/w) Formulation 7 DI (15% w/w), DMSO (15% Separates into two phasesw/w), PC (5% w/w), BA (2.7% w/w), Petroleum (10% w/w), Mineral Oil(50.5% w/w), Rofecoxib (2% w/w) Formulation 8 DI (15% w/w), DMSO (15%The Xanthan gum does not w/w), PC (5% w/w), BA (2.7% mix at all. w/w),Lanolin (10% w/w), Mineral Oil (40.5% w/w), PBS/Xanthan Gum 0.75% (10%w/w), Rofecoxib (2% w/w) Formulation 9 DI (32.8% w/w), PC (10.9%Insoluble w/w), BA (5.9% w/w), DMSO (34.8% w/w), AT (10.9% w/w),Rofecoxib (4.3% w/w) Formulation 10 DI (28.4% w/w), PC (9.4% Insolublew/w), BA (5.1% w/w), AT (9.4% w/w), OA (9.4% w/w), DMSO (34.2% w/w),Rofecoxib (3.7% w/w) Formulation 11 DI (32.8% w/w), PC (10.9% Insolublew/w), BA (5.9% w/w), DGME (10.9% w/w), DMSO (34.8% w/w), Rofecoxib (4.3%w/w) Formulation 12 DI (28.4% w/w), PC (9.4% Insoluble w/w), BA (5.1%w/w), DGME (9.4% w/w), DMSO (34.2% w/w), OA (9.4% w/w), Rofecoxib (3.7%w/w) Formulation 13 DI (29.6% w/w), PC (9.8% Insoluble w/w), BA (5.3%w/w), DGME (9.8% w/w), DMSO (31.4% w/w), AT (9.8% w/w), Rofecoxib (3.9%w/w) Formulation 14 DI (23.8% w/w), PC (7.9% Insoluble w/w), BA (4.2%w/w), DGME (7.9% w/w), DMSO (28.8% w/w), AT (7.9% w/w), OA (7.9% w/w),DOME (7.9% w/w), Rofecoxib (3.1% w/w) Formulation 15 DI (9.5% w/w), PC(3.1% soluble w/w), BA (1.7% w/w), DMSO (72.6% w/w), Rofecoxib (12.7%w/w) Formulation 16 DI (32.8% w/w), PC (10.9% Insoluble w/w), BA (5.9%w/w), DMSO (34.8% w/w), OA (10.9% w/w), Rofecoxib (4.3% w/w) Formulation17 DI (34.3% w/w), PC (11.4% Soluble w/w), BA (6.1% w/w), DMSO (31.9%w/w), PS-20 (11.4% w/w), Rofecoxib (4.5% w/w) Formulation 18 DI (32.8%w/w), PC (10.9% Soluble w/w), BA (5.9% w/w), DMSO (34.8% w/w), PS20(10.9% w/w), Rofecoxib (4.3% w/w) Formulation 19 DI (27.1% w/w), PC (9%Soluble after sonication w/w), BA (4.8% w/w), OA (9% w/w), PS20 (9%w/w), DMSO (37% w/w), Rofecoxib (3.6% w/w) Formulation 20 DI (24.9%w/w), PC (8.3% insoluble before sonication; w/w), BA (4.4% w/w), ATafter sonication- soluble (8.3% w/w), OA (8.3% w/w), PS20 (8.3% w/w),DMSO (33.9% w/w), Rofecoxib (3.3% w/w) Formulation 21 DI (24.9% w/w), PC(8.3% insoluble before sonication; w/w), BA (4.4% w/w), aftersonication- soluble DGME (8.3% w/w), OA (8.3% w/w), PS20 (8.3% w/w),DMSO (33.9% w/w), Rofecoxib (3.3% w/w) Formulation 22 DI (23% w/w), PC(7.6% insoluble before sonication; w/w), BA (4.1% w/w), aftersonication- soluble DGME (7.6% w/w), AT (7.6% w/w), OA (7.6% w/w), PS20(7.6% w/w), DMSO (31.3% w/w), Rofecoxib (3% w/w) Formulation 23 DI(29.6% w/w), PC (9.8% slightly insoluble before w/w), BA (5.3% w/w),sonication; after sonication- DMSO (31.4% w/w), PS80 soluble (9.8% w/w),OA (9.8% w/w), Rofecoxib (3.9% w/w) Formulation 24 DI (60.7% w/w), PC(20.2% slightly insoluble before w/w), BA (10.9% w/w), sonication; aftersonication- Rofecoxib (8% w/w) soluble Formulation 25 DI (32.8% w/w), PC(10.9% slightly insoluble before w/w), BA (5.9% w/w), sonication; aftersonication- DMSO (34.8% w/w), PS60 soluble (10.9% w/w), Rofecoxib (4.3%w/w) Formulation 26 DI (32.8% w/w), PC (10.9% slightly insoluble beforew/w), BA (5.9% w/w), sonication; after sonication- DMSO (34.8% w/w),PS60 soluble (10.9% w/w), OA (10.9% w/w), Rofecoxib (4.3% w/w)Formulation 27 DI (50.5% w/w), PC (16.8% insoluble w/w), BA (9% w/w), OA(16.8% w/w), Rofecoxib (6.7% w/w) Formulation 28 DI (38.7% w/w), PC(12.9% After sonication it is w/w), BA (6.9% w/w), OA soluble and stable(12.9% w/w), DMSO (23.3% w/w), Rofecoxib (5.1% w/w) Formulation 29 DI(14% w/w), PC (4.6% after sitting overnight, w/w), BA (2.5% w/w), OAseparates (4.6% w/w), DMSO (8.4% w/w), Glycerol monostearate (4.6% w/w),Mineral Oil (1.8% w/w), Rofecoxib (59% w/w) Formulation 30 DI (14.8%w/w), PC (4.9% Thick emollient that w/w), BA (2.6% w/w), OA does notseparate (4.9% w/w), DMSO (8.9% w/w), Bees wax (3.4% w/w), Lanoline(9.9% w/w), Mineral Oil (48.1% w/w), Rofecoxib (1.9% w/w) Formulation 31DI (30.7% w/w), PC (10.2% Ointment that does not w/w), BA (5.5% w/w), OAseparate (10.2% w/w), DMSO (18.5% w/w), Lanoline (20.5% w/w), Rofecoxib(4.1% w/w) Formulation 32 DI (14.6% w/w), PC (4.8% Separates even afterw/w), BA (2.6% w/w), OA addition of 20% SDS (7.3% w/w), DMSO (8.8% w/w),Lanoline (9.7% w/w), Olive Oil (49.9% w/w), Rofecoxib (1.9% w/w)Formulation 33 DI (14.5% w/w), PC (4.8% separates even after w/w), BA(2.6% w/w), OA addition of 50 μL PS80 (7.2% w/w), DMSO (8.7% w/w),Lanoline (4.8% w/w), Olive Oil (55% w/w), Rofecoxib (1.9% w/w)Formulation 34 DI (15.3% w/w), PC (5.1% This combination works w/w), BA(2.7% w/w), OA well (7.6% w/w), DMSO (9.2% w/w), PEG-400 (57.7% w/w),Rofecoxib (2% w/w) Formulation 35 DI (15% w/w), PC (5% lanoline causesseparation w/w), DMSO (9.1% w/w), BA (2.6% w/w), Oleic Acid (5% w/w),Lanolin (10% w/w), Min. Oil (51.3% w/w), Rofecoxib (2% w/w) Formulation36 DI (15% w/w), PC (5% Bees wax stablizes the w/w), DMSO (9.1% w/w),ointment BA (2.6% w/w), Oleic Acid (5% w/w), Lanolin (10% w/w), Min. Oil(47.8% w/w), Bees Wax (3.5% w/w), Rofecoxib (2% w/w) Formulation 37 DI(15% w/w), PC (5% Slight separation of oil w/w), BA (2.6% w/w), at thetop DMSO (9.1% w/w), Oleic Acid (5% w/w), Lanolin (5% w/w), Min. Oil(47.8% w/w), Bees Wax (3.5% w/w), Rofecoxib (2% w/w) Formulation 38Rofecoxib (2% w/w), DI (15% mineral oil causes solvent w/w), PC (5%w/w), BA system to separate and (2.6% w/w), DMSO (9.1% lanolin causesprecipitation w/w), Oleic Acid (5% w/w), of rofecoxib Lanolin (10% w/w),Min. Oil (45.45% w/w), Bees Wax (1.75% w/w) Formulation 39 Rofecoxib (2%w/w), DI (15% lanolin causes solvent w/w), PC (5% w/w), BA system toseparate (2.6% w/w), DMSO (9.1% w/w), Oleic Acid (5% w/w), Lanolin (5%w/w), Min. Oil (47.8% w/w), Bees Wax (1.75% w/w) Formulation 40 DI (15%w/w), PC (5% lanolin causes solvent w/w), BA (2% w/w), DMSO system toseparate (10% w/w), OA (5% w/w), PEG-400 (51% w/w), Lanoline (10% w/w),Rofecoxib (2% w/w) Formulation 41 DI (15% w/w), PC (5% Soluble w/w), BA(2% w/w), DMSO (10% w/w), OA (5% w/w), PEG-400 (61% w/w), Rofecoxib (2%w/w) Formulation 42 DI (15% w/w), PC (5% Separates w/w), BA (2% w/w),DMSO (10% w/w), OA (5% w/w), PEG-400 (40% w/w), IMTD/IM (20.995% w/w),Rofecoxib (2% w/w) Formulation 43 DI (15% w/w), PC (5% Separates w/w),BA (2% w/w), DMSO (10% w/w), OA (5% w/w), PEG-400 (40% w/w), IMTD/ IM(19% w/w), SDS (2% w/w), Rofecoxib (2% w/w) Formulation 44 DI (15% w/w),PC (5% precipitation after three w/w), BA (2% w/w), DMSO days (10% w/w),OA (5% w/w), PEG-400 (40% w/w), PGD (21% w/w), Rofecoxib (2% w/w)Formulation 45 DI (15% w/w), PC (5% Sonicated until warm but w/w), BA(2% w/w), DMSO then it clumps when it (10% w/w), OA (5% w/w), coolsPEG-400 (40% w/w), PGD (12% w/w), Lanoline (9.5% w/w), Rofecoxib (2%w/w) Formulation 46 DI (15% w/w), PC (5% precipitation after three w/w),BA (2% w/w), DMSO days (10% w/w), OA (5% w/w), PEG-400 (46% w/w), PS80(15% w/w), Rofecoxib (2% w/w) Formulation 47 DI (15% w/w), PC (5%Precipitates w/w), BA (2% w/w), DMSO (10% w/w), OA (5% w/w), PEG-400(40% w/w), PPG (21% w/w), Rofecoxib (2% w/w) Formulation 48 DI (15%w/w), PC (5% precipitation after three w/w), BA (2% w/w), DMSO days (10%w/w), OA (5% w/w), PEG-400 (46% w/w), PS20 (15% w/w), Rofecoxib (2% w/w)Formulation 49 DI (15% w/w), PC (5% insoluble but may be w/w), BA (2%w/w), DMSO soluble with more (10% w/w), OA (5% w/w), homogenizationPEG-400 (42% w/w), Bees Wax (3.1% w/w), PS80 (15% w/w), Rofecoxib (2%w/w) Formulation 50 DI (15% w/w), PC (5% Soluble after 7 days at w/w),BA (2% w/w), DMSO RT (10% w/w), OA (5% w/w), PEG-400 (40% w/w), EA (21%w/w), Rofecoxib (2% w/w) Formulation 51 DI (15% w/w), PC (5%precipitation after three w/w), BA (2% w/w), DMSO days (10% w/w), OA (5%w/w), PEG-400 (40% w/w), DGME (21% w/w), Rofecoxib (2% w/w) Formulation52 DI (15% w/w), PC (5% precipitation after three w/w), BA (2% w/w),DMSO days (10% w/w), OA (5% w/w), PEG-400 (50% w/w), Alfa- Terpinol (11%w/w), Rofecoxib (2% w/w) Formulation 53 DI (15% w/w), PC (5% Solubleafter 7 days at w/w), BA (2% w/w), DMSO RT (10% w/w), OA (5% w/w),PEG-400 (49% w/w), DIA (12% w/w), Rofecoxib (2% w/w) Formulation 54 DI(15% w/w), PC (5% precipitation after three w/w), BA (2% w/w), days DMSO(10% w/w), OA (5% w/w), PEG-400 (40% w/w), DS (21% w/w), Rofecoxib (2%w/w) Formulation 55 DI (15% w/w), PC (5% precipitation after three w/w),BA (2% w/w), DMSO days (10% w/w), OA (5% w/w), PEG-400 (49% w/w), M24D(12% w/w), Rofecoxib (2% w/w) Formulation 56 DI (15% w/w), PC (5%precipitation after three w/w), BA (2% w/w), DMSO days (10% w/w), OA (5%w/w), PEG-400 (40% w/w), Mineral Oil (21% w/w), Rofecoxib (2% w/w)Formulation 57 DI (15% w/w), PC (5% Soluble w/w), BA (2% w/w), DMSO (10%w/w), OA (5% w/w), DIA (10% w/w), PEG-400 (52% w/w), Rofecoxib (1% w/w)Formulation 58 DI (15% w/w), PC (5% Soluble w/w), BA (2% w/w), DMSO (10%w/w), OA (5% w/w), DIA (10% w/w), PEG-400 (51% w/w), Rofecoxib (2% w/w)Formulation 59 DI (15% w/w), PC (5% Soluble w/w), BA (2% w/w), DMSO (15%w/w), OA (5% w/w), DIA (10% w/w), PEG-400 (47% w/w), Rofecoxib (1% w/w),Formulation 60 DI (15% w/w, PC (5% OA causes precipitation w/w), BA (2%w/w), DMSO of rofecoxib (15% w/w), EA (20% w/w), DIA (20% w/w), AT (10%w/w), OA (5% w/w), Rofecoxib (4% w/w) Formulation 61 DI (17.4% w/w), PC(5.8% OA causes precipitation w/w), BA (2.3% w/w), of rofecoxib DMSO(17.4% w/w), EA (23.2% w/w), DIA (23.2% w/w), OA (5.8% w/w), Rofecoxib(4.6% w/w) Formulation 62 DI (15% w/w), PC (5% AT causes precipitationw/w), BA (2.3% w/w), of rofecoxib DMSO (15% w/w), EA (30% w/w),Rofecoxib (4% w/w), DIA (12% w/w), AT (10% w/w), Bees Wax (3% w/w),Menthol (2.5% w/w), Eucalyptus (1.2% w/w) Formulation 63 DI (15% w/w),PC (5% Rofecoxib precipitates w/w), BA (2.3% w/w), after 24 hours DMSO(15% w/w), EA (30% w/w), DIA (12% w/w), Rofecoxib (4% w/w), PS20 (15%w/w), Menthol (2.5% w/w), Formulation 64 DI (15.4% w/w), PC (5.1%Precipitates w/w), BA (2.5% w/w), DMSO (20.6% w/w), DIA (12.3% w/w),PS20 (15.4% w/w), DGME (25.2% w/w), Rofecoxib (3% w/w) Formulation 65 DI(15.9% w/w), PC (5.3% Rofecoxib is soluble w/w), BA (2.6% w/w), DMSO(21.2% w/w), DIA (12.7% w/w), PS20 (15.9% w/w), DGME (17.5% w/w), OA(5.3% w/w), Rofecoxib (3.1% w/w) Formulation 66 DI (11.3% w/w), PC (5.4%Precipitates w/w), BA (2.7% w/w), DMSO (21.6% w/w), DIA (12.9% w/w),PS20 (16.2% w/w), PGD (10.8% w/w), OA (5.4% w/w), DGME (10.2% w/w),Rofecoxib (3.2% w/w) Formulation 67 DI (15.4% w/w), PC (5.1% Slightprecipitation w/w), BA (2.5% w/w), DMSO (20.6% w/w), DIA (12.3% w/w),PS20 (15.4% w/w), AT (10.3% w/w), DGME (14.8% w/w), Rofecoxib (3% w/w)Formulation 68 DI (15.4% w/w), PC (5.1% Precipitates w/w), BA (2.5%w/w), DMSO (20.6% w/w), DIA (12.3% w/w), PS20 (15.4% w/w), AT (10.3%w/w), OA (5.1% w/w), DOME (9.7% w/w), Rofecoxib (3% w/w) Formulation 69DI (15.4% w/w), PC (5.1% Precipitates w/w), B A (2.5% w/w), DMSO (20.6%w/w), DIA (12.3% w/w), PS20 (15.4% w/w), PG (25.2% w/w), Rofecoxib (3%w/w) Formulation 70 DI (15.4% w/w), PC (5.1% Precipitates w/w), BA (2.5%w/w), DMSO (20.6% w/w), DIA (12.3% w/w), PS20 (15.4% w/w), OA (5.1%w/w), PPG (20.1% w/w), Rofecoxib (3% w/w) Formulation 71 DI (15.3% w/w),PC (5.1% Precipitates w/w), BA (2.5% w/w), DMSO (20.4% w/w), DIA (12.2%w/w), PS20 (15.3% w/w), PGD (10.2% w/w), DOME (14.7% w/w), Rofecoxib (4%w/w) Formulation 72 DI (15.7% w/w), PC (5.2% Precipitates w/w), BA (2.6%w/w), DMSO (20.9% w/w), DIA (12.5% w/w), PS20 (15.7% w/w), PGD (10.4%w/w), AT (12.5% w/w), Rofecoxib (4.1% w/w) Formulation 73 DI (15.8%w/w), PC (5.2% Precipitates w/w), BA (2.6% w/w), DMSO (21.1% w/w), DIA(12.6% w/w), PS20 (15.8% w/w), PGD (10.5% w/w), AT (12.6% w/w),Rofecoxib (3.1% w/w) Formulation 74 DI (15.7% w/w), PC (5.2% Solublew/w), BA (2.6% w/w), DMSO (21% w/w), DIA (12.6% w/w), PS20 (15.7% w/w),PGD (10.5% w/w), AT (5.2% w/w), DGME (7.8% w/w), Rofecoxib (3.1% w/w)Formulation 75 DI (15.7% w/w), PC (5.2% Soluble w/w), BA (2.6% w/w),DMSO (21% w/w), DIA (12.6% w/w), PS20 (15.7% w/w), PGD (10.5% w/w), AT(7.8% w/w), DGME (5.2% w/w), Rofecoxib (3.1% w/w) Formulation 76 DI(15.6% w/w), PC (5.2% some precipitation w/w), BA (2.6% w/w), DMSO(20.8% w/w), DIA (12.5% w/w), PS20 (15.6% w/w), AT (10.4% w/w), DGME(15% w/w), Rofecoxib (2% w/w) Formulation 77 DI (14.1% w/w), PC (4.7%Works ok but separates w/w), BA (2.3% w/w), a little DMSO (18.8% w/w),DIA (11.3% w/w), PS20 (14.1% w/w), PGD (9.4% w/w), OA (4.7% w/w), DGME(8.9% w/w), Rofecoxib (1.8% w/w), Lanoline (9.4% w/w) Formulation 80 DI(15.62% w/w); PC (5.2% Soluble w/w); BA (2.6% w/w); DMSO (20.83% w/w),OA (5.2% w/w); DIA (12.5% w/w); PS20 (15.62% w/w); DGME (8.85% w/w); PGD(10.41% w/w); Rofecoxib (2.08% w/w); Spearmint (0.34% w/w); Eucalyptusoil (0.69% w/w) Formulation 82 DI (15.62% w/w); PC (5.2% Soluble w/w);BA (2.6% w/w); DMSO (20.83% w/w); OA (5.2% w/w), DIA (12.5% w/w); PS20(15.62% w/w); DGME (19.27% w/w); Rofecoxib (2.08% w/w); Spearmint (0.34%w/w); Eucalyptus oil (0.69% w/w) Formulation 83 DI (15.62% w/w); PC(5.2% Soluble w/w); BA (2.6% w/w); DMSO (20.83% w/w); DIA (12.5% w/w);PS20 (15.62% w/w); DGME (8.85% w/w); PGD (10.41% w/w); AT (5.2% w/w);Rofecoxib (2.08% w/w); Spearmint (0.34% w/w); Eucalyptus oil (0.69% w/w)Formulation 85 DI (15% w/w); PC (5% Soluble w/w); BA (2.5% w/w); DMSO(20% w/w), DIA (12% w/w), DGME (18.5% w/w); PS20 (15% w/w); OA (5% w/w),Hydoxypropyl cellulose 100,000 (4% w/w); Rofecoxib 2% (2% w/w);Eucalyptus Oil (0.33% w/w); Spearmint Oil (0.67% w/w) Formulation 86 DI(15.62% w/w); PC (5.2% light precipitation w/w); BA (2.6% w/w);overnight DMSO (10.41% w/w); OA (7.81% w/w); PEG-400 (55.2% w/w);Rofecoxib (2.08% w/w), Spearmint (0.34% w/w), Eucalyptus oil (0.69% w/w)Formulation 87 DI (15.62% w/w); PC (5.2% light precipitation w/w); BA(2.6% w/w); overnight DMSO (10.41% w/w); OA (5.2% w/w); PEG-400 (35.94%w/w); EA (21.87% w/w); Rofecoxib (2.08% w/w); Spearmint (0.34% w/w);Eucalyptus oil (0.68% w/w) Formulation 88 DI (15.54% w/w); PC (5.18%precipitation after three w/w); BA (2.59% w/w), days DMSO (10.36% w/w);OA (7.77% w/w); PEG-400 (43% w/w); DIA (12.43% w/w); Rofecoxib (2.07%w/w); Spearmint (0.34% w/w), Eucalyptus oil (0.69% w/w) Formulation 89DI (15.62% w/w); PC (5.2% precipitation after three w/w); BA (2.08%w/w); days DMSO (10.41% w/w); OA (5.2% w/w), PEG-400 (47.91% w/w); DIA(10.41% w/w); Rofecoxib (2.08% w/w); Spearmint (0.34% w/w), Eucalyptusoil (0.69% w/w) Formulation 90 DI (15.62% w/w); PC (5.2% heavyprecipitation w/w); BA (2.6% w/w); overnight DMSO (20.83% w/w); OA (5.2%w/w); DIA (12.5% w/w); PS20 (15.62% w/w); DGME (18.22% w/w); Rofecoxib(3.12% w/w); Spearmint (0.34% w/w); Eucalyptus oil (0.69% w/w)Formulation 91 DI (15.62% w/w); PC (5.2% light precipitation w/w); BA(2.6% w/w); overnight DMSO (20.83% w/w); DIA (12.5% w/w); PS20 (15.62%w/w); DGME (7.81% w/w); PGD (10.41% w/w); AT (5.2% w/w); Rofecoxib(3.12% w/w); Spearmint (0.34% w/w); Eucalyptus oil (0.69% w/w)Formulation 92 DI (15.62% w/w), PC (5.2% heavy precipitation w/w); BA(2.6% w/w); overnight DMSO (20.83% w/w); DIA (12.5% w/w); PS20 (15.62%w/w); DGME (5.2% w/w); PGD (10.41% w/w); AT (7.81% w/w), Rofecoxib(3.12% w/w); Spearmint (0.34% w/w); Eucalyptus oil (0.69% w/w)Formulation 93 DI (15.62% w/w); PC (5.2% precipitation after three w/w);BA (2.6% w/w), days DMSO (10.41% w/w); OA (5.2% w/w), PEG-400 (45.31%w/w); DIA (12.5% w/w); Rofecoxib (2.08% w/w); Spearmint (0.34% w/w);Eucalyptus oil (0.69% w/w)

Example 2, Release of Rofecoxib from Topical Solution

A Franz cell apparatus was used to test for release of rofecoxib fromthe disclosed rofecoxib topical formulations. The Franz cell apparatushas six cells, which exhibit different volumes, diameters, and areas(Table 6). The area of cells 1-5 is 8.73 cm². Membranes used fordiffusion release were Durapure PDVF (0.45 μm, Millipore). The receptormedia is 70% PBS (pH 7.4) from Gibco, 15% dimethyl isosorbide and 15%propylene carbonate. A circulating water bath was set to maintain thereceptor media at 32 degrees Celsius. The cells were pre-warmed for 30minutes before the samples were added to the donor chamber.

TABLE 6 Franz Cell Parameters Cell Volume (mL) Diameter (mm) Area (cm²)1 11.0  4.0/14.0 1.54 2 10.9 14.5/14.5 1.7 3 11.2 16.5/16.5 2.1 4 11.1515.0/15.0 1.8 5 10.8  14.5/14.75 1.7 6 11.15 15.0/16.0 1.7617

The first 5 cells were loaded with either a fixed volume of a topicalsample equal to 300 μl (6 mg) or was loaded with 1 ml sample with 20 mgof rofecoxib. The 6th cell was used as a negative control for rofecoxibdiffusion e.g. the sixth cell was loaded with the same volume of the ofthe excipients without rofecoxib.

300 μL samples were taken at 10, 20, 30, 40, 50, 60, 75, 90, 105, 120and 180 minutes. The receptor volume was replaced with fresh prewarmedreceptor fluid directly after the sample was taken. The samples andcontrol were diluted 1:10 (100 ul:900 ul) into methanol. After using thecontrol to blank the spectrophotometer (as in Example 1), the absorbanceof the samples was determined at 279.1 nm.

Calculation of rofecoxib after 90 minutes of diffusion: To calculate theamount of rofecoxib that diffused in 90 minutes per cell, the OD readingwas multiplied by the extinction coefficient of rofecoxib (29.06) timesthe dilution (10×) times the volume of the cell (11 ml) and, divided by1000 to determine the milligrams of rofecoxib that diffused in 90minutes. For example, for cell #1, which has an absorbance at 279.1 nmof 1.5033, the amount of rofecoxib that diffused=((1.5033)(29.06)(10)(11)/1000=4.805 mg. The total amount of rofecoxibthat diffused was determined by adding the amount of rofecoxib thatdiffused through each cell. The average amount of rofecoxib thatdiffused in 90 minutes was determined by dividing the total amount ofrofecoxib that diffused by the number of cells. #1 (279.1 nm)O.D.=1.5033*29.06*10*11/±1000=4.805 mg.

Calculating the diffusion per cm²: The diffusion per square area in 90minutes was calculated by dividing the total amount of rofecoxib thatmigrated through cells 1 to 5 and dividing by the total membrane area(Take the total of all rofecoxib through the five membranes in 90minutes and divide by the area of the total membrane area of cells 1-5(8.73 cm²). For example, if 22.95 mg of rofecoxib diffused, and themembrane area of the cells is 8.73 cm², the amount of rofecoxib thatdiffused per square centimeter is 2,626 mg/cm².

Calculating the flux rate: The flux rate or the amount of rofecoxib thatdiffused per cm² per hour (μg/cm²/hour) was determined. Two pointswithin the linear range of a graph of time versus amount of rofecoxibwere utilized, the first point after which diffusion became linear, orT=1 and a second point 30 minutes later, or T=2. The diffusion rate isthe total mg of rofecoxib diffused at T=2 (i.e. 60 minutes) minus mg oftotal rofecoxib diffused at T=1 (30 minutes) times 2 (to make it andtotal mg per hour) divided by the total cm². In the example aboveexample, at 30 minutes the diffused rofecoxib=9.062 mg and at 60minutes=19.731 mg; (19.731 mg-9.062 mg)×2=21.338 mg/hour divided by8.7389 cm²=2.44 mg/hr/cm². Flux of various rofecoxib topicalcompositions: Franz cells were employed to evaluate the flux of variousrofecoxib topical compositions. Initial experiments used the followingreceptor media: 90% PBS pH 87.4 and 10% MP; 90% PBS 7.4 with 10%methanol. These receptor medias caused rofecoxib to precipitate out ofsolution. The experiments described below used Franz cell media of 70%PBS pH 7.4 with 15% DI and 15 PC as receptor media; enabling rofecoxibto stay in solution. The below experiments evaluated the diffusion ofthe rofecoxib topical compositions through 0.45 μm Durapore®,polyvinylidene fluoride (PVDF) membranes (obtained from EMI) Millipore).

A composition (Formulation 1) containing acetone (49% w/w), benzylalcohol (49% w/w), and rofecoxib (2% w/w) resulted in a flux rate of1.52 mg/h/cm². This composition allowed 93% of rofecoxib to diffusewithin 90 minutes.

A composition (Formulation 2) containing DI (49% w/w), PC (49% w/w), androfecoxib (2% w/w) resulted in a flux rate of 1.39 mg/h/cm², Thiscomposition allowed 82% of rofecoxib to diffuse within 90 minutes.

A composition (Formulation 3) containing 39% w/w DI, 12% w/w PC, 39% w/wDMSO, 8% w/w BA, and 2% w/w rofecoxib resulted in a flux rate of 15.31mg/h/cm². This composition allowed 76.51% of rofecoxib to diffuse within90 minutes.

A composition (Formulation 6) containing 15% w/w DI, 5% w/w PC, 15% w/wDMSO 2.7% w/w BA, 10% w/w lanoline, 50.3% mineral oil, and 2.0% w/wrofecoxib resulted in a flux rate of 0.359 mg/h/cm². This compositionallowed 18.8% of rofecoxib to diffuse within 90 minutes. Without beingbound by theory, the lower percent of rofecoxib diffusion and flux ratemay be attributed to the fact that the organic solvents moved throughthe membrane faster than rofecoxib, leading to crystallization ofrofecoxib, and an ending of rofecoxib diffusion. This experimenthighlighted the challenges of developing a rofecoxib topicalcomposition.

A composition (Formulation 35) containing 15% w/w DI, 5% w/w PC; 9% w/wDMSO, 3% w/w BA, 5% w/w oleic acid, 10% w/w lanolin, 51% w/w mineraloil, and 2.0% w/w rofecoxib resulted in a flux rate of 0.919 mg/h/cm².This composition allowed 48.7 of rofecoxib to diffuse within 90 minutes.

A composition (Formulation 36) containing 15% w/w DI, 5% w/w PC, 9% w/wDMSO, 3% w/w BA, 5% w/w oleic acid, 10% w/w lanolin, 48% w/w mineraloil, 4% w/w bees wax, and 2.0% w/w rofecoxib resulted in a flux rate of0,099 mg/h/cm². This composition allowed 12.85% of rofecoxib to diffusewithin 90 minutes.

A composition (Formulation 41) containing 15% w/w DI, 5% w/w PC, 10%w/w, 5% w/w oleic acid, 2. % w/w BA, 61% w/w PEG, and 2.0% w/w rofecoxibresulted in a flux rate of 0.229 mg/h/cm². This composition allowed36.22% of rofecoxib to diffuse within 90 minutes.

A composition (Formulation 57) containing 15% w/w DI, 5% w/w PC, 10% w/wDMSO, 5% w/w oleic acid, 2% w/w BA, 10% DIA, 52% w/w PEG, and 1.0% w/wrofecoxib resulted in a flux rate of 2.19 mg/h/cm². This compositionallowed 75.71% of rofecoxib to diffuse within 90 minutes (FIG. 3). Incomparison, Voltaren® Gel which comprises diclofenac has a flux rate of0.604 mg/cm²/hour and 24.4% of diclofenac diffused in 90 minutes.

A composition (Formulation 58) containing 15% w/w DI, 5% w/w PC, 10% w/wDMSO, 2% w/w BA, 5% w/w oleic acid, 10% w/w DIA, 51% w/w PEG, and 2.0%w/w rofecoxib resulted in a flux rate of 4.4 mg/h/cm². This compositionallowed 13.26% of rofecoxib to diffuse within 90 minutes.

Future experiments will test the ability of the compositions to diffusethrough pig skin and human skin. Animal studies using conventional painmodels, including but not limited to, the formalin model, tail-flickmodel, hot plate model, complete Freund's Adjuvant (CFA) model, nervegrowth factor (NGF) model, Carrageenan Paw Edema (CPE) model, andmonoiodoacetate (MIA)-induced osteoarthritis joint pain model. Rofecoxibtopical compositions will be evaluated in humans that exhibit one ormore of the following of arthritis, osteoarthritis, juvenile rheumatoidarthritis, joint pain due to injury e.g. ankle sprains, sports injuries,carpal tunnel syndrome, ankle sprains, rheumatoid arthritis,inflammation, low back pain, ankylosing spondylitis, psoriaticarthritis, tennis elbow, headache, and migraine. Rofecoxib topicalcompositions will be also be evaluated in pre-clinical studies asmandated by the Food and Drug Administration for topical formulations.

Example 3. Release of Rofecoxib in Human Skin

The ability of rofecoxib topical compositions to penetrate human skinwas evaluated using a Franz diffusion cell. Retention of rofecoxib inthe epidermal and dermal skin compartments was also evaluated.

A 0.54 cm² section of human cadaver skin was mounted over a Franz cellreceptor well. The receptor well was filled with receptor fluidcomprising 3.30 mi, of 2% w/w hydroxypropyl-β-cyclodextrine (HPBCD) and0.01% w/w NaN₃. 5 μL of a rofecoxib topical composition was introducedinto the donor well. Fluid samples were abstracted from the receptorafter 4 hours, 8 hours, and 22 hours and analyzed for the presence ofrofecoxib.

The rofecoxib topical compositions in Table 7 were evaluated.

TABLE 7 Rofecoxib Topical Compositions Name of Composition CompositionFormulation DI (15% w/w); PC (5% w/w); BA (2.5% w/w); DMSO 80 (20% w/w);DIA (12% w/w); PS20 (15% w/w); PGD (10% w/w); OA (5% w/w); DGME (8.5%w/w); Rofecoxib (2% w/w); Spearmint (0.33% w/w); Eucalyptus oil (0.67%w/w) Formulation DI (15% w/w); PC (5% w/w); BA (2.5% w/w); DMSO 82 (20%w/w); DIA (12% w/w); PS20 (15% w/w); DGME (18.5% w/w); OA (5% w/w);Rofecoxib (2% w/w); Spearmint (0.33% w/w); Eucalyptus oil (0.67% w/w)Formulation DI (15% w/w); PC (5% w/w); BA (2.5% w/w); DMSO 83 (20% w/w);DIA (12% w/w); PS20 (15% w/w); PGD (10% w/w); AT (5% w/w); DGME (8.5%w/w); Rofecoxib (2% w/w); Spearmint (0.33% w/w); Eucalyptus oil (0.67%w/w)

The amount of rofecoxib delivered over time, the percentage of rofecoxibdelivered over time, and the flux of rofecoxib absorbed through the skinare reported in Tables 8, 9, and 10, respectively. FIG. 4 shows thedelivered dose of rofecoxib over time. FIG. 6 shows the percentage ofrofecoxib delivered over time. FIG. 7 shows the flux of the rofecoxibtopical compositions.

18% of rofecoxib in the Formulation 80 diffused after 22 hours. 20.5% ofrofecoxib in Formulation 82 diffused after 22 hours. 24.2% of rofecoxibin Formulation 83 diffused after 22 hours. In contrast, only 6% and 8%,respectively, of diclofenac in the commercially available Voltaren® geland PENNSAID® topical MAIDS diffuse within 24 hours. Topical rofecoxibcompositions exhibit three times better diffusion suggesting bettertissue penetration than diclofenac compositions. A rofecoxib topicalcomposition is also desirable, because due to rofecoxib's half-life of17 hours, a rofecoxib topical composition is suitable for once-a-dayadministration.

Tables 8 and 9 also show the amount of rofecoxib delivered to the dermisand epidermis and the percentage of rofecoxib delivered to the dermisand the epidermis, respectively. FIG. 5 shows the delivered dose ofrofecoxib to the dermis and epidermis. FIG. 6 shows the percentage ofrofecoxib delivered to the dermis and epidermis. Each of the rofecoxibtopical compositions evaluated penetrated the dermis and epidermis.

TABLE 8 Rofecoxib Delivered Dose (reported in μg/cm²) 4 hours 8 hours 22hours Epidermis Dermis Standard Standard Standard Standard StandardFormulation Dose Error Dose Error Dose Error Dose Error Dose ErrorFormulation 4.05 0.6 20.65 1.07 32.79 4.88 7.08 1.4 2.49 0.2 80Formulation 12.7 0.85 20.8 1.56 37.31 2.52 13.69 2.45 4.29 0.74 82Formulation 12.41 0.59 21.44 1.38 44.01 3.19 18.58 3.64 3.31 0.49 83

TABLE 9 Percentage of Rofecoxib Delivered (reported as %) 4 hours 8hours 22 hours Epidermis Dermis Percent Standard Percent StandardPercent Standard Percent Standard Percent Standard Formnlation DeliveredError Delivered Error Delivered Error Delivered Error Delivered ErrorFormulation 2.23 0.33 11.36 0.59 18.03 2.68 3.89 0.77 1.37 0.11 80Formulation 6.99 0.47 11.44 0.86 20.52 1.39 7.53 1.35 2.36 0.41 82Formulation 6.82 0.32 11.79 0.76 24.21 1.75 10.22 2 1.82 0.27 83

TABLE 10 Flux of Rofecoxib Compositions (reported in μg/cm²/hr) 4 hours8 hours 22 hours Standard Standard Standard Formulation Flux Error FluxError Flux Error Formulation 1.01 0.15 4.15 0.28 0.87 0.29 80Formulation 3.18 0.21 2.02 0.19 1.18 0.19 82 Formulation 3.1 0.15 2.260.34 1.61 0.22 83

Example 4. Stability Testing of Rofecoxib Topical Compositions

The solubility of rofecoxib in the presence of solvents selected fromthe Food and Drug Administration's Inactive Ingredient Database (IID)for use in a topical product was evaluated. Table 11 shows thesolubility of rofecoxib in various solvents.

TABLE 11 Solubility of Rofecoxib in Various Solvents by High PerformanceLiquid Chromatography Solubility of Rofecoxib Solvent (% w/w) 1.25%Niacinamide (Aqueous) No observable solubility 10% Sodium Lauryl Sulfate(Aqueous) *   No observable solubility * Dehydrated Alcohol Noobservable solubility Diethyl Sebacate No observable solubilityDiethvlene Glvcol Monoethvl Ether * 0.5-1.0 Diisoproovl Adipate Noobservable solubility Dimethyl Isosorbide *   2.5-3.5% Ethyl Acetate  <0.5% Glycervl Monooleate No observable solubility Hydrochloric Acid(0.1N) No observable solubility Laureth-4 No observable solubilityMedium Chain Triglycerides No observable solubilityN-Methvl-Pvrrolidone * 4.4-5.4 Oleyl Alcohol No observable solubilityPEG400 * 1.0-1.5 Polysorbate 80 No observable solubility PropyleneCarbonate * 3.4-4.3 Propylene Glycol Diacetate <0.5 Sodium Hydroxide(0.1N) * No observable solubility Sorbitol Solution No observablesolubility Water pH 3 No observable solubility Water pH 5.5 Noobservable solubility Water pH 7.4 No observable solubility * ColorChange Observed, colorless to yellow

The stability of rofecoxib was assessed by HPLC after storage for twoweeks at 40° C. and for two weeks at 50° C. Table 12 shows thesolubility of rofecoxib in various solvents after two weeks at 40° C.and at 50° C. Rofecoxib, which was solubilized in the solvents in Table12, remained soluble for two weeks at 40° C. and 50° C.

TABLE 12 Solubility of Rofecoxib after 2 weeks at 40° C. and 50° C.Rofecoxib Concentration (% w/w) T = 2 weeks T = 2 weeks Solvent T = 0weeks 40° C. storage 50° C. storage Acetone 2.549 2.549 2.549 Benzylalcohol 1.447 1.474 1.470 Diethylene glycol 0.687 0.672 0.677 monoethylether Dimethyl isosorbide 2.641 2.515 2.511 Ethyl acetate 0.465 0.4790.476 N-methyl-2- 5.046 5.057 5.055 pyrrolidone PEG 400 1.013 0.9870.993 Propylene Carbonate 3.471 3.456 3.463 Propylene Glycol 0.519 0.5270.520 Diacetate

Future experiments will test the stability of the rofecoxib topicalcompositions of the disclosure at additional time points, including 1month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8months, 9 months, 10 months, 11 months, and 12 months.

Example 5. Effect of Rofecoxib Topical Compositions on Pain andInflammation

A study in rats was conducted to evaluate the effect of rofecoxibtopical compositions on pain and inflammation. On study day 0, 55 MaleSprague Dawley rats were weighed and randomized by body weight.Subsequently animals were anesthetized with isoflurane and administereda 0.04 mL, intra-articular injection of Freund's incomplete adjuvantsupplemented by Mycobacterium butyricum into the right knee.Administration of Freund's incomplete adjuvant and Mycobacteriumbutyricum causes symptoms of arthritis in the rats, including pain andinflammation. On study day 2, animals underwent gait testing and wererandomized into groups based on gait scores.

On study day 3, animals were administered a rofecoxib topicalcomposition (e.g., Formulation 85), a rofecoxib vehicle that containedthe rofecoxib topical composition's solvent system but lacked rofecoxib,or oral rofecoxib (10 mg/kg). As a control, naïve rats were notadministered Freund's incomplete adjuvant and were administered avehicle comprising 15.15% w/w dimethyl isosorbide. 5.05% w/w propylenecarbonate, 2.53% w/w benzyl alcohol, 10.10% of 10% DMSO, 10.1%diisopropyl adipate, 45.45% w/w polyethylene glycol 400, 7.58% w/w oleicacid, 3.03% RPC, 0.33% eucalyptus oil, and 0.68% w/w spearmint oil.Formulation 85 contained 2% w/w rofecoxib, 15% w/w dimethyl isosorbide,5% w/w propylene carbonate. 2.5 w/w benzyl alcohol, 20% w/w dimethylsulfoxide, 12% w/w diisopropyl adipate, 18.5% w/w diethylene glycolmonoethyl ether, 15.0 polysorbate 20 (PS20), 5% w/w oleic acid, 4% w/whydroxypropyl cellulose (MW=100,000 Da), 0.33% w/w eucalyptus oil, and0.67% w/w spearmint oil. Formulation 85 vehicle contained 15.31% w/wdimethyl isosorbide, 5.1% w/w propylene carbonate, 2.55% benzyl alcohol,20.41% w/w DMSO, 12.24% diisopropyl adipate, 18.88% w/w diethyleneglycol monoethyl ether, 15.31% w/w PS20, 5.1% w/w oleic acid, 4.08% w/wHPC, 0.34% w/w eucalyptus oil, and 0.68% w/w spearmint oil. The animalswere administered the rofecoxib topical composition once daily.

Table 13 shows the study groups evaluated.

TABLE 13 Study Groups Dose Dose Compound and/ (% or Dose Vol Conc GroupN or Treatment mg/kg) Regimen (ml) (mg/ml) 1 5 Naive 0 Top, QD, D 3 0.10 4 10 Formulation 85 Vehicle 0 Top, QD, D 3 0.1 0 5 10 Formulation 852% Top, QD, D 3 0.1 2.4 6 10 rofecoxib 10 mg/kg PO, QD, D 3 5 ml/kg 9

Table 14 shows the study calendar.

TABLE 14 Study Calendar Day −7 Day −6 Day −5 Day −4 Day −3 Day −2 Day −1Distribute rats on arrival into groups for acclimation Day 0 Day 1 Day 2Day 3 Day 4 Day 5 Day 6 Assign Weigh, Dose, Gait, randomization gait,Gait, necroscopy numbers, randomize Bleed inject animals by adjuvant IAgait into right knee

Gait testing was performed four hours, 8 hours, and 24 hourspost-dosing. Gait measurements were conducted by applying ink to theventral surface of the foot and documenting weight bearing duringmovement (footprints) across paper. Rear feet of rats were placed in inkand then rats were placed on paper and allowed to walk the full length.This process was repeated as necessary to generate 4 clear, evenly inkedfootprint pairs representing the overall pattern of gait. Gait (footprints) will be scored visually as follows (descriptions refer todiseased leg): 0=Normal, approximately equal ink staining to normal paw;1=Slight limp/pain=reduced inking area relative to the normal paw, butno full regions or structures are missing; 2=Mild limp/pain=Printextends to the end or near to the end of the “curlicue” structure. Ifnormal paw has very little heel staining (rat walks mainly on toes/ballof foot), then slightly less staining; 3=Moderate limp/pain=toes andfull ball of foot, extending to the top of the “curlicue” foot. Ifnormal paw has very little heel staining (rat walks mainly on toes/ballof foot), then toes with small portion of ball of foot; 4=Markedlimp/pain=toes and partial ball of foot, no heel or posterior foot. Ifnormal paw has very little heel staining (rat walks mainly on toes/ballof foot), then toes only; 5=Severe limp/pain=toes only, no ball of foot,no heel. If normal paw has very little heel staining (rat walks mainlyon toes/ball of foot), then partial toes or nonspecific marks; 6=Hoppingor Carrying leg, no footprint is evident.

Knee caliper measurements were taken daily. Caliper measures of rightand left knee diameters were performed on assigned days using a DigitrixII micrometer caliper (Fowler & NSK). Baseline knee caliper measurementswere taken using one knee with values rounded to one-thousandth of aninch. Measurements were confirmed as clinically normal by comparisonwith historical values for rats based on a range of body weights.Baseline measurements were then applied to both knees, and these valuesremain with the animal so long as the knee is clinically, normal.

FIG. 8 shows the effect of the rofecoxib topical composition Formulation85 on gait score. By eight hours post dosing of Formulation 85, the gaitof the treated rats improved. Surprisingly, rofecoxib topicalformulation 85 caused a greater improvements in rat gait than the oralrofecoxib formulation. FIG. 9 show the area under the curve of gaitscore calculated from 4 hours to 22 hours. A Kruskal-Wallis post-hocanalysis using Dunn's nonparametric comparison revealed that incomparison to the Formulation 85 vehicle control, Formulation 85significantly reduced the gait score (†p≤0.05). These resultscollectively show that topical rofecoxib compositions reduce pain.

FIG. 10 shows right knee caliper measurements after administration ofthe rofecoxib topical composition Formulation 85. FIG. 11 shows thepercent change in right knee caliper measurement from baseline. Theaverage right knee caliper change from baseline measured in inches forthe rofecoxib topical composition Formulation 85 is displayed in FIG.12. In comparison to vehicle control treated rats, rats treated withrofecoxib topical compositions displayed a reduction in right kneecaliper measurement, consistent with a reduction in inflammation. FIG.13A, FIG. 13B, and FIG. 13C show the mean area under the curve for kneecaliper measurement. A one-way analysis of variance (ANOVA) using Tukeyand Dunnett's methods showed that in comparison to the Formulation 85vehicle control, Formulation 85 significantly reduced inflammation(†p≤0.05).

Example 6. Pharmacokinetic Study of Rofecoxib Formulation in MiniatureSwine

A study in Hanford miniature swine was conducted to evaluate thepharmacokinetics of rofecoxib topical compositions. The Hanfordminiature swine used in the study were males, aged 0.2 to 0.4 years,which weighed between 10 and 20 kg.

The experimental design for the study is shown in Table 15 below.

TABLE 15 Experimental Design Dose Dose Dose Dose Number of Conc. volumelevel Treatment Route animals (mg/mL) (mL/kg) (mg/kg) Oral RofecoxibPO^(a) 2 M 0.10 2 0.2 Formulation 85 Topical^(b) 2 M 20 1.25^(c) NA^(c)

The dose level of the oral arm of this pharmacokinetic study was basedon the lowest effective human dose of rofecoxib previously approved bythe FDA for use in humans, 12.5 mg. The dose levels of the test articlesin the topical administration arms were selected based on the expecteddermal penetration to provide circulating blood levels similar to orbelow the oral administration.

Animals in the oral rofecoxib group were administered oral rofecoxibonce daily via oral gavage followed by up to 10 mL of tap water tofacilitate swallowing. Animals in the topical rofecoxib group wereadministered Formulation 85 once on Dosing Phase Day 1 and twice-daily,on Dosing Phase Days 2 to 7, 8 hours apart, via dermal administration to10% body surface area.

Dose sites were observed for skin irritation using the Modified Draizescoring system detailed below in Table 16,

TABLE 16 Modified Draize Scoring System Category Score DescriptionErythema 0 None 1 Slight 2 Well-defined 3 Moderate or severe 4 Severe orslight eschar formation (injuries in depth) Edema 0 None 1 Very slight 2Slight (well-defined edges) 3 Moderate (raised >1 mm) 4 Severe(raised >1 mm and extending beyond the area of exposure)

Whole blood (2 mL) was collected on all study animals on Dosing PhaseDays 1 and 7 at each designated time point (Table 17) via directvenipuncture of the jugular vein (or other appropriate vessel). Synovialfluid was collected from both knees of each animal at euthanasia.

TABLE 17 Pharmacokinetic Sample Collection Scheme Pharmacokinetic SampleCollection Scheme Groups Intervals Target Time Points All Dosing PhasePredose, 0.25, 0.5, 1, 2, 4, 8 (prior to 2^(nd) Days 1 and 7 dose onDosing Phase Day 7), 12 and 24 hours post dose

The following pharmacokinetic parameters were evaluated:

TABLE 18 Pharmacokinetic Parameters Parameter Description C_(max)Maximum observed concentration of rofecoxib T_(max) Time of C_(max)relative to dosing T_(1/2) Calculated elimination half-life AUC Areaunder concentration by time curve Accumulation Comparison of values fromDosing Phase Day 1 to Day 7

Pharmacokinetic Methods: A non-compartmental pharmacokinetic (PK)approach consistent with either oral or topical route of administrationwas used to estimate PK parameters in Watson LIMS (version 7.5). Allparameters were generated from individual concentrations in plasmawhenever practical. BQL data was set to zero for the samples at time 0(pre-dose) and was excluded for all other time points post dose for thecalculation of toxicokinetic parameters. All concentration values werein ng/mL, and all time points were in hours. Nominal doses and samplingtimes were used. The observed maximum plasma concentration (C_(max)),time of C_(max) (T_(max)), and AUC (area under the concentration vs.time curve) were determined directly from the data during the entire 24hour time interval post dosing. Standard deviation and coefficient ofvariation determined by Watson LIMS were computed when possible. Foranalyses that were not supported by Watson, i.e. custom comparisons,Excel was used and the statistics were reported as determined by excelalgorithms. Note that in either case, when the number of data points wasless than three, standard deviation and coefficient of variation couldnot be calculated.

Safety: After administration of Formulation 85, all animals in the studyexhibited a Modified Draize score of 0, indicating that the formulationdid not produce skin irritation.

Pharmacokinetic Results: Table 19 and FIG. 14A shows the plasmaconcentrations of rofecoxib over time after administration of oralrofecoxib or topical rofecoxib Formulation 85 on dosing day 1. Table 19and FIG. 14B shows the plasma concentrations of rofecoxib over timeafter administration of oral rofecoxib or topical rofecoxib Formulation85 on day 7.

TABLE 19 Plasma Concentration of Rofecoxib over Time Day 1 Day 7Treatment Rofecoxib Concentration (ng/mL) Oral Formulation OralFormulation Time (hours) Rofecoxib 85 Rofecoxib 85 0 0 0 1.74 3.49 0.250 0 1.57 4.11 0.5 3.09 0 8.15 7.51 1 20.2 0.442 21.4 5.97 2 62.4 1.84143 9.43 4 91.4 14.5 80 11.1 8 31.5 0.326 16.95 6.58 12 15.9 0.426 14.74.24 24 3.15 0.535 1.68 28.5

Table 20A shows the plasma concentration of 5-OH-rofecoxib, a metaboliteof rofecoxib after administration of Formulation 85 or oral rofecoxib.FIG. 15A shows the plasma concentration of 5-OH and the plasmaconcentration of rofecoxib after administration of oral rofecoxib. FIG.1513 shows the plasma concentration of 5-OH and the plasma concentrationof rofecoxib after administration of Formulation 85.

TABLE 20A Plasma Concentration of Rofecoxib and 5-OH-rofecoxib over timeOral Rofecoxib Formulation 85 5-OH- 5-OH- Rofecoxib Rofecoxib RofecoxibRofecoxib Time (hours) (ng/mL) (ng/mL) (ng/mL) (ng/mL) 0 1.74 0 3.49 00.25 1.57 0 4.11 0 0.5 8.15 2.25 7.51 2.89 1 21.4 2.33 5.97 0 2 143 5.959.43 0 4 80 6.18 11.1 0 8 16.95 1.74 6.58 0 12 14.7 1.47 4.24 0 24 1.680 28.5 3.39

The data shows that rofecoxib administered in a topical formulation isabsorbed.

The amount of rofecoxib and 5-OH-Rofecoxib in synovial fluid was alsoquantitated. Table 2013 shows the amount of rofecoxib and 5-OH rofecoxibin synovial fluid after administration of oral rofecoxib or Formulation85.

TABLE 20B Plasma Concentration of Rofecoxib and 5-OH- rofecoxib overtime in the synovial fluid Oral Rofecoxib Formulation 85 Rofecoxib(ng/mL) 0 0 5-OH Rofecoxib (ng/mL) 11.4 0

The pharmacokinetic parameters Cmax, Tmax, and AUC were also evaluated(Table 21).

TABLE 21 Pharmacokinetic Parameters for Rofecoxib after Administrationof Oral Rofecoxib or Formulation 85 Mean Values, Plasma Rofecoxib OralRofecoxib Formulation 85 Oral and Topical Day 7/Day 1 Day 7/Day 1Parameter Units Day 1 Day 7 Ratio Day 1 Day 7 Ratio Cmax ng/mL 91.4 1431.57 14.5 29.9 2.06 Tmax Hours 4.00 2.00 0.500 4.00 14.0 3.50 AUCng*Hours/mL 610 579 0.950 39.3 237 6.04 Cmax/Dose ng/mL/mg 22.9 35.81.57 0.580 0.598 1.03 AUC/Dose ng*Hours/mL/mg 153 145 0.950 1.57 4.753.02 Original Dose mg 4.00 4.00 1.00 25.0 50.0 2.00

Formulation 85 obtained a Cmax of 15.9% of the oral formulation on day 1and 20.9% of the oral formulation on day 7. Formulation 85 obtained anAUC of 6.4% of the oral formulation on Day 1 and 41% of the oralformulation on day 7.

A comparison of the pharmacokinetic parameters of Formulation 85 tocommercially available diclofenac gel (available as VOLTAREN® gel) anddiclofenac sodium topical solution (available as PENNSAID™) is shown inTable 22. The pharmacokinetic parameters obtained from the miniatureswine data can be extrapolated to humans by taking into account thedifference in surface area between humans and swine. Humans are threetimes larger than swine, so humans would, to a first-approximation,exhibit a 3-fold dilution in exposure compared to swine.

TABLE 22 Formulation 85's Pharmacokinetic Parameters compared toCommercially Available Topical NSAID formulations Formulation 85 (25VOLTAREN ® (120 PENNSAID ™ (40 mg twice per day) mg 4 times a day) mg 4times a day) Cmax 20.9%  2.2% 0.85% Tmax 14.0%  10%   4% AUC  41% 19.7%19.4%

As Table 22 shows, Formulation 85 is more bioavailable than the NSAIDtopical formulations VOLTAREN® and PENNSAID™_(.)

Example 7. A Phase 1, Randomized, Double-Blind, Placebo-Controlled, DoseEscalation Study Evaluating the Safety, Tolerability, Pharmacokinetics,and Pharmacodynamics of Topical Rofecoxib in Subjects withOsteoarthritis of a Knee

This Phase 1 trial evaluates the safety, tolerability, pharmacokinetics,and pharmacodynamics of single and multiple topical applications ofRofecoxib in subjects with OA of the knee. The incidence, relatedness,severity, and duration of treatment adverse events (TEAEs) is evaluated.The maximum tolerated dose of topical rofecoxib is determined. Subjectsare administered a topical rofecoxib composition or placebo to the kneeaffected with OA.

Pharmacokinetic properties of rofecoxib in plasma are also evaluated,including the maximum observed plasma concentration (Cmax),dose-adjusted Cmax (Cmax/dose), time to maximum observed plasmaconcentration (Tmax), area under the plasma concentration versus timecurve from time zero to the last quantifiable concentration (AUC₀₋₄),the dose adjusted AUC_(0-t) (AUC_(0-t)/dose), AUC from time zero toinfinity (AU_(0-∞)), the dose-adjusted AUC_(0-∞) (AUC_(0-∞)/dose),terminal elimination rate constant (t_(1/2)), terminal half-life,apparent clearance (CL/F), and volume of distribution (Vz/F).Descriptive statistics for pharmacokinetics parameters by treatmentgroup includes number of observations, arithmetic mean, standarddeviation, arithmetic coefficient of variation (% ACV), geometric mean,median, geometric % CV, minimum, and maximum. Dose proportionality isexplored.

The pharmacodynamics (PD) of topical rofecoxib is evaluated by examiningseveral exploratory endpoints, including serum N-propeptide of collagenIIA (PIIANP), C-telopeptide of type II collagen (CTX-II), pain andphysical functioning as assessed by the Western Ontario and McMasterUniversities Arthritis Index (WOMAC), and magnetic resonance (MR)imaging data. The pre-treatment values for these endpoints is comparedto post-treatment measurements and both the absolute and percent changefrom baseline is summarized. Descriptive statistics for PD endpoints bytime point and by treatment group will include number of observations,arithmetic mean, standard deviation, arithmetic coefficient of variation(% CV), median, minimum, and maximum. An exploratory analysis of PK/PDendpoints is performed.

A schedule of a single-ascending dose cohort schedule of assessments ispresented in Table 23. A schedule of a multiple-ascending dose cohortschedule of assessments is presented in Table 24.

TABLE 23 Study Calendar of a Single-ascending dose cohort schedule ofassessments VISIT NAME SCREENING DAY 1^(K) DAY 2_(A) DAY 8 DAY 29_(A)VISIT NUMBER 1^(I) 2 3 4 5 TIME POST DOSE PRE 15 30 60 90 2 4 NA DOSE^(J) 0 MIN MIN MIN MIN HRS HRS ALLOWABLE WINDOW −28 to −1 +/−2 +/−3 +/−5+/−5 +/−5 +/−5 +/−1 +3 days Min Min Min Min Min Min Day Days InformedConsent X Demography X Medical History X Prior & Concomitant X X X X X XTreatments Physical Examination X X X Height X Weight X X X VitalSigns^(B) X X X X X X X X X 12-Lead ECG X X X Tibial-Femoral XRadiographs^(C) Safety Laboratory X X X Tests^(D) Urine Drug Screen XEligibility Review X X Randomization X VAS X WOMAC^(F) X X PK BloodSample X X X X X X X PIIANP Blood Sample X X CTX-II Urine Sample X XBanked Biospecimen X X X Sample-Serum^(G) Banked Biospecimen X Sample IPAdministration X Adverse Events _(H) X X X X X X X X X X _(A)Day 2 andDay 29 Visits may be conducted via telephone. ^(B)Vital signs collectionincludes temperature, seated blood pressure, and pulse rate^(C)Tibial-femoral x-rays to confirm the diagnosis of OA and theKellgren & Lawrence Grade must be of acceptable quality and acquiredwithin 6 months prior to Screening ^(D)Safety laboratory testingincludes hematology, chemistry, and urinalysis E For women ^(F)The WOMACshould be administered at the beginning of the visit prior to completingother procedures ^(G)Optional banked biospecimen collection _(H) AdverseEvents are captured starting at time of consent. Any Adverse Eventsduring Screening and Day 1 will be captured and noted as part of medicalhistory ^(I)Screening procedures may be completed across multiple daysduring the 28 day screening period and do not need to be conducted onconsecutive days ^(J) All predose screening assessments should beconducted within 2 hours prior to IP administration ^(K)Subjects may bedischarged after at least 2 hours of safety observation following thelast procedure

TABLE 24 Schedule of a Multiple-ascending Dose Cohort Schedule ofAssessments VISIT NAME DAY DAY DAY DAY DAY DAY DAY DAY DAY SCREENING1^(K) 2^(A) 8 ^(K) 15 ^(K) 22 ^(K) 29 50^(A) 90^(M) 180^(M) VISIT NUMBER1^(I) 2 3 4 5 6 7 8 9 10 TIME POST FIRST DOSE PRE- 15 30 60 90 2 4 NADOSE ^(J) 0 MIN MIN MIN MIN HRS HRS ALLOWABLE VISIT WINDOW −28 to −1+/−2 +/−3 +/−5 +/−5 +/−5 +/−5 +/−1 +/−1 +/−1 +/−1 +3 +/−7 +/−7 days MinMin Min Min Min Min Day ^(L) Day ^(L) Day ^(L) Day Days Days DaysInformed X Consent Demography X Medical X History Prior & X X X X X X XX X X X Concomitant Treatments Physical X X X X X X Examination Height XWeight X X X X X X X X Vital Signs^(B) X X X X X X X X X X X X X 12-LeadX X X X X X ECG Tibial- X Femoral Radiographs ^(C) Safety X X X X X XLaboratory Tests^(D) Follicle X Stimulating Hormone Test^(E) Urine DrugX Screen MRI X X X Eligibility X X Review Randomization X VAS XWOMAC^(F) X X X X X PK Blood X X X X X X X X X X X Sample PIIANP X X X XX X Blood Sample CTX-II Urine X X x X X X X Sample Banked X X X X XBiospecimen Sample- Serum^(G) Banked X X X Biospecimen Sample- SynovialFluid^(G) IP X X X Administration Adverse X X X X X X X X X X X X X XEvents _(H) ^(A)Day 2 arid Day 50 visits may be conducted via telephone^(B)Vital signs (temperature, seated blood pressure, and pulse rate)should be collected pre-dose and 30 minutes after dosing on Days 8, 15,and 22 ^(C) Tibial-femoral x-rays to confirm the diagnosis of OA andKellgren & Lawrence Grade must be of acceptable quality and acquiredwithin 6 months prior to Screening ^(D)Safety laboratory testingincludes hematology, chemistry, and urinalysis ^(E)For women ^(F)TheWOMAC should be administered at the beginning of the visit prior tocompleting other procedures ^(G)Optional banked biospecimen collection_(H) Adverse Events are captured starting at time of consent. AnyAdverse Events during Screening and Day 1 will be captured and noted aspart of medical history ^(I)Screening procedures may be completed acrossmultiple days during the 28 day screening period and do not need to beconducted on consecutive days ^(J) All predose screening assessmentsshould be conducted within 2 hours prior to IP administration ^(K)Subjects may be discharged after at least 2 hours of safety observationfollowing the last procedure ^(L) There should be minimum of 7 daysbetween the IA injections

NUMBERED EMBODIMENTS OF THE DISCLOSURE

Notwithstanding the appended claims, the disclosure sets forth thefollowing numbered embodiments:

1. A topical composition comprising a therapeutically effective amountof rofecoxib dissolved in a solvent system comprising one or morepharmaceutically acceptable solvents.2. The topical composition of embodiment 1, wherein the pharmaceuticallyacceptable solvent system comprises one or more pharmaceuticallyacceptable solvents selected from the group consisting of acetone (AC),2-methylpentane-2,4-diol (M24D), alpha-terpineol (AT), benzyl alcohol(BA), diethyl sebacate (DS), diethylene glycol monoethyl ether (DGME),diisopropyl adipate (DIA), dimethyl sulfoxide (DMSO), ethyl acetate(EA), isopropyl tetradecanoate (IPTD), N-methyl-2-pyrrolidone (MP),polyethylene glycol 400 (PEG), polysorbate 20 (PS20), polysorbate 80(PS80), propylene glycol diacetate (PGD), propylene glycol (PPG),isosorbide dimethyl ether, and propylene carbonate.3, The topical composition of embodiment 1, wherein the solvent systemcomprises isosorbide dimethyl ether (DI) and propylene carbonate (PC).4. The topical composition of embodiment 3, wherein the solvent systemfurther comprises DMSO.5. The topical composition of embodiment 3, wherein the solvent systemcomprises from about WAV DI to about 20% w/w DI and from about 3% w/w PCto about 8% w/w PC.6. The topical composition of embodiment 3, wherein the solvent systemcomprises about 15% w/w DI and about 5% w/w PC.7. The topical composition of embodiment 3, wherein the solvent systemcomprises BA.8, The topical composition of embodiment 3, wherein the solvent systemcomprises DMSO.9. The topical composition of embodiment 3, wherein the solvent systemcomprises DIA.10. The topical composition of embodiment 3, wherein the solvent systemcomprises PS20.11. The topical composition of embodiment 3, wherein the solvent systemcomprises BA, DMSO, DIA, and PS20.12. The topical composition of embodiment 3, wherein the solvent systemcomprises about 15% w/w DI, about 5% w/w PC, about 3% w/w BA, about 20%w/w DMSO, about 12% w/w DIA, and about 15% w/w PS20.13. The topical composition of embodiment 1, wherein the therapeuticallyacceptable amount of rofecoxib is up to 5 bio w/w.14. The topical composition of embodiment 1, comprising one or moreadditional ingredients selected from the group consisting of ahumectant, a chelating agent, a UV absorption agent, a moisturizingagent, an excipient, a preservative, a thickening agent, a siliconecontaining compound, an essential oil, a structuring agent, a vitamin, apharmaceutical ingredient, and an antioxidant.15. The topical composition of embodiment 1, comprising oleic acid.16. A method of applying the topical composition of embodiment 1 toskin, comprising topically applying the topical composition ofembodiment 1.17. A method of reducing inflammation, comprising topically applying thetopical composition of embodiment 1.18. A method of treating arthritis, comprising topically applying thetopical composition of embodiment 1.19. A method of treating acute pain, comprising topically applying thetopical composition of embodiment 1.20. A method of treating migraines, comprising topically applying thetopical composition of embodiment 1.21. The topical composition of embodiment 1, wherein the topicalcomposition is selected from Formulations 1-77, 80, 82, 83, and 85-93.22. The topical composition of embodiment 1, wherein the topicalcomposition is Formulation 85.

INCORPORATION BY REFERENCE

All references, articles, publications, patents, patent publications,and patent applications cited herein are incorporated by reference intheir entireties for all purposes. However, mention of any reference,article, publication, patent, patent publication, and patent applicationcited herein is not, and should not be taken as, an acknowledgment orany form of suggestion that they constitute valid prior art or form partof the common general knowledge in any country in the world.

1-27. (canceled)
 28. A topical composition comprising a therapeuticallyeffective amount of from 0.1% w/w to 2.5% w/w rofecoxib, dissolved in amixture of between about 0.1% w/w and about 15% w/w isosorbide dimethylether (DI), between about 0.1% w/w and about 5% w/w propylene carbonate(PC), and between about 12% w/w and about 15% w/w diisopropyl adipate(DIA), and a moisturizing agent.
 29. The topical composition of claim28, further comprising one or more pharmaceutical ingredients.
 30. Thetopical composition of claim 29, wherein the one or more pharmaceuticalingredients comprise an antihistamine.
 31. The topical composition ofclaim 29, wherein the one or more pharmaceutical ingredients comprise ananti-inflammatory agent.
 32. The topical composition of claim 29,wherein the one or more pharmaceutical ingredients comprise ananalgesic.
 33. The topical composition of claim 29, the one or morepharmaceutical ingredients comprise a hair growth stimulant.
 34. Thetopical composition of claim 29, wherein the one or more pharmaceuticalingredients comprise an antineoplastic or an anti-cancer active.
 35. Thetopical composition of claim 28, further comprising about 30% w/w toabout 45% w/w PEG-400.
 36. The topical composition of claim 28, furthercomprising between about 5% w/w to about 8% w/w oleic acid.
 37. Thetopical composition of claim 35, further comprising between about 5% w/wto about 8% w/w oleic acid.
 38. The topical composition of claim 28,wherein the amount of DIA is about 12% w/w or about 15% w/w.
 39. Thetopical composition of claim 38, further comprising between about 5% w/wto about 8% w/w oleic acid.
 40. The topical composition of claim 38,further comprising about 30% w/w to about 45% www PEG-400.
 41. Thetopical composition of claim 40, further comprising between about 5% w/wto about 8% w/w oleic acid.
 42. A method of reducing inflammation,comprising topically applying a therapeutically effective amount of thetopical composition of claim 28 to the skin of a patient in needthereof, wherein said skin is at the site of inflammation.
 43. A methodof reducing inflammation, comprising topically applying atherapeutically effective amount of the topical composition of claim 35to the skin of a patient in need thereof, wherein said skin is at thesite of inflammation.
 44. A method of reducing inflammation, comprisingtopically applying a therapeutically effective amount of the topicalcomposition of claim 37 to the skin of a patient in need thereof,wherein said skin is at the site of inflammation.
 45. A method oftreating arthritis in a joint, comprising topically applying atherapeutically effective amount of the topical composition of claim 28to the skin of a patient in need thereof, at the arthritic joint.
 46. Amethod of treating psoriatic arthritis, comprising topically applying atherapeutically effective amount of the topical composition of claim 34to the skin of a patient in need thereof.
 47. A method of treatingmigraine, comprising topically applying a therapeutically effectiveamount of the topical composition of claim 32 to the skin of a patientin need thereof.